Aerospace Toxicology: An Overview - Federal Aviation …€¦ · · 2012-05-311 AerospAce...
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Arvind K. Chaturvedi Civil Aerospace Medical Institute Federal Aviation Administration Oklahoma City, OK 73125 April 2009 Final Report Aerospace Toxicology: An Overview DOT/FAA/AM-09/8 Office of Aerospace Medicine Washington, DC 20591 OK-09-0434-JAH Federal Aviation Administration
Transcript of Aerospace Toxicology: An Overview - Federal Aviation …€¦ · · 2012-05-311 AerospAce...
Arvind K. Chaturvedi
Civil Aerospace Medical InstituteFederal Aviation AdministrationOklahoma City, OK 73125
April 2009
Final Report
Aerospace Toxicology:An Overview
DOT/FAA/AM-09/8Office of Aerospace MedicineWashington, DC 20591
OK-09-0434-JAH
Federal AviationAdministration
NOTICE
This document is disseminated under the sponsorship of the U.S. Department of Transportation in the interest
of information exchange. The United States Government assumes no liability for the contents thereof.
___________
This publication and all Office of Aerospace Medicine technical reports are available in full-text from the Civil Aerospace Medical Institute’s publications Web site:
www.faa.gov/library/reports/medical/oamtechreports
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Technical Report Documentation Page 1. Report No. 2. Government Accession No. 3. Recipient's Catalog No.
DOT/FAA/AM-09/8 4. Title and Subtitle 5. Report Date
April 2009 Aerospace Toxicology: An Overview 6. Performing Organization Code
7. Author(s) 8. Performing Organization Report No. Chaturvedi AK
9. Performing Organization Name and Address 10. Work Unit No. (TRAIS) FAA Civil Aerospace Medical Institute P.O. Box 25082 11. Contract or Grant No. Oklahoma City, OK 73125
12. Sponsoring Agency name and Address 13. Type of Report and Period Covered Office of Aerospace Medicine Federal Aviation Administration 800 Independence Ave., S.W. Washington, DC 20591 14. Sponsoring Agency Code
15. Supplemental Notes This work was accomplished under the approved task AM-B-09-TOX-202. 16. Abstract The field of aerospace toxicology is composed of aerospace and toxicology. The term aerospace—that is, the environment extending above and beyond the surface of the Earth—is also used to represent the combined fields of aeronautics and astronautics. Aviation is another term frequently and interchangeably used with aerospace and aeronautics and is explained as the science and art of operating powered aircraft. Toxicology is the basic science of poisons. It deals with the adverse effects of substances on living organisms. Any substance could be poisonous, depending upon its exposure amount and frequency.
Although toxicology borrows knowledge from the fields of biology, chemistry, immunology, pathology, physiology, and public health, the most closely related field to toxicology is pharmacology. Economic toxicology, environmental toxicology, and forensic toxicology are 3 main branches of toxicology. Toxicology is a multidisciplinary field. Aerospace toxicology could be considered closely related to aerospace medicine.
In this overview, a literature search for the period of 1960–2007 was performed, covering aerospace toxicology- related subject matter. The article is divided into the sections of introduction, agricultural aviation (aerial application), aviation combustion toxicology, postmortem aviation forensic toxicology, cabin air contamination, and references. Further readings are also suggested. It is anticipated that this overview article would be a reference source for the topics related to aerospace toxicology.
17. Key Words 18. Distribution Statement
Aerospace Toxicology, Aerial Application, CombustionToxicology, Aviation Forensic Toxicology, Cabin Air Quality, Pilot Fatalities, Aviation Accident Investigation
Document is available to the public through the Defense Technical Information Center, Ft. Belvoir, VA 22060; and the National Technical Information Service, Springfield, VA 22161
19. Security Classif. (of this report) 20. Security Classif. (of this page) 21. No. of Pages 22. Price Unclassified Unclassified 48
Form DOT F 1700.7 (8-72) Reproduction of completed page authorized
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ACKNOWLEDGMENTS
The author �s grateful to Kr�st� J. Craft for ass�st�ng �n the comp�lat�on of references and for prov�d�ng
cr�t�cal remarks and suggest�ons �n the organ�zat�onal and grammat�cal structures of the manuscr�pt.
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SYMBOLS, ABBREVIATIONS, AND ACRONYMS
λ ------------------------ (lambda) wavelength 2,4-D ------------------ dichlorophenoxyacetic acid 5-HIAA --------------- 5-hydroxyindole-3-acetic acid 5-HTOL --------------- 5-hydroxytryptophol AAFS ----------------- American Academy of Forensic Sciences AsMA ----------------- Aerospace Medical Association C ----------------------- concentration CAA ------------------- Civil Aviation Authority CAEE -------------------- average effective exposure concentration CAMI ----------------- Civil Aerospace Medical Institute CBI -------------------- 1-cyano-2-benzoisoindole (1-cyano[f]benzoisoindole) CFR ------------------- Code of Federal Regulations CN¯ ------------------- cyanide ion CO --------------------- carbon monoxide CO2 -------------------- carbon dioxide cyano-MetHb --------- cyanomethemoglobin DDT ------------------- dichlorodiphenyltrichloroethane EUROCAE------------ European Organisation for Civil Aviation Equipment FAA ------------------- Federal Aviation Administration FED ------------------- Fractional Effective Dose FTC -------------------- Fractional Toxic Concentration GAO ------------------- General Accounting Office HbA1c ------------------ hemoglobin A1c
HCN ------------------- hydrogen cyanide HEPA: ---------------- high efficiency particulate air HHb ------------------- deoxyhemoglobin K ----------------------- constant MetHb ----------------- methemoglobin NTSB ----------------- National Transportation Safety Board OxyHb ---------------- oxyhemoglobin PCR ------------------- polymerase chain reaction ppm -------------------- parts per million SOFT ------------------ Society of Forensic Toxicologists, Inc. SSRIs ------------------ selective serotonin reuptake inhibitors sulph-MetHb --------- sulphmethemoglobin t ------------------------ gas exposure time TCPs ------------------ tricresyl phosphates td ----------------------- time-to-death tHb --------------------- total hemoglobin THC ------------------- Δ9- tetrahydrocannabinol ti ------------------------ time-to-incapacitation TMPP ----------------- trimethyl propane phosphate TSB -------------------- Transportation Safety Board of Canada
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CONTENTS1 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 AGRICULTURAL AVIATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.1 General�ty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.2 Pest�c�dal Tox�cology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2.3 Mult�-Agr�cultural Chem�cals and Organ�c Solvents/Surfactants . . . . . . . . . . . . . . . . . . . . . . . 2 2.4 Appl�cat�on Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.5 Exposure Mon�tor�ng . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 AVIATION COMBUSTION TOXICOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1 Combust�on, F�re, and Smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.2 Smoke Gases and Tox�c�ty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.3 A�rcraft Mater�al Test�ng . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.4 Gases and The�r Interact�ve Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.4.1 Gas Interact�ons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.4.2 Fract�onal Effect�ve Dose (FED) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3.4.3 Carboxyhemoglob�n (COHb) and Blood Cyan�de Ion (CN¯) . . . . . . . . . . . . . . . . . . . 10 3.4.4 COHb and Blood CN¯ Interact�ve Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.4.5 COHb and Blood CN¯ �n F�re-Involved A�rcraft Acc�dent Fatal�t�es . . . . . . . . . . . . . . . 15 3.4.6 Analyt�cal Results Interpretat�on . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.4.6.1 Analys�s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.4.6.2 COHb Concentrat�ons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.4.6.3 CN¯ Concentrat�ons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.4.6.4 MetHb, Cyano-MetHb, and Sulfmethemoglob�n (Sulf-MetHb) . . . . . . . . . . . . 164 POSTMORTEM AVIATION FORENSIC TOXICOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 4.1 Introductory Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 4.2 Analyt�cal Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 4.3 COHb and Blood CN¯ Concentrat�ons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 4.4 Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.5 Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.5.1 Commonly Used and Abused Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.5.2 SSRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.5.3 F�rst-Generat�on H
1 Ant�h�stam�n�cs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
4.5.4 Other Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.5.4.1 Seleg�l�ne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.5.4.2 S�ldenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.5.4.3 Vardenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.5.4.4 Butalb�tal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.6 Elevated Glucose and HbA
1c . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5 CABIN AIR CONTAMINATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 5.1 Introductory Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 5.2 A�rcraft Cab�n A�r . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 5.3 Space Veh�cle Cab�n A�r . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 5.4 A�rcraft Eng�ne O�ls, Hydraul�c Flu�ds, and Lubr�cants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
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AerospAce Toxicology: An overview
All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.
—Paracelsus
1 INTRODUCTION
Aerospace tox�cology �s composed of 2 words, aerospace and tox�cology. The former could be denoted as “the total env�ronment extend�ng above and beyond the surface of the planet Earth” (28). Aerospace �s also used to represent the comb�ned fields of aeronaut�cs and astronaut�cs. The field of aeronaut�cs �s the art and sc�ence of fl�ght through the atmosphere (28), whereas astronaut�cs �s a relat�vely new field related to the art and sc�ence of space fl�ght (26). Av�at�on �s another term frequently and �nterchangeably used w�th aerospace and aeronaut�cs and �s expla�ned as the sc�ence and art of operat�ng powered a�rcraft (269).
Tox�cology �s the bas�c sc�ence of po�sons. It deals w�th the adverse effects of substances on l�v�ng organ�sms. Any substance could be po�sonous, depend�ng upon �ts exposure amount and frequency (106, 125, 182).
Tox�cology borrows knowledge from the fields of b�ology, chem�stry, �mmunology, pathology, phys�ol-ogy, and publ�c health. The most closely related field to tox�cology �s pharmacology (182). The tox�cology field can eas�ly be branched �nto econom�c tox�cology, env�ronmental tox�cology, and forens�c tox�cology. In v�ew of the mult�d�sc�pl�nary nature of tox�cology, one can deduce that aerospace tox�cology �s closely related to aerospace med�c�ne, wh�ch �s a spec�alty field of general med�c�ne (27) and �s concerned w�th the health and med�-cal problems of man �n av�at�on and space fl�ghts (199). Alternat�vely, av�at�on med�c�ne could be cons�dered as the branch of prevent�ve med�c�ne that deals w�th the spec�al problems of fly�ng, both w�th�n and outs�de the atmosphere (46).
In th�s overv�ew, a l�terature search for the per�od of 1960–2007 was performed cover�ng aerospace tox�cology-related subject matter. In add�t�on to the �ntroduct�on, the art�cle �s d�v�ded �nto head�ngs of agr�cultural av�a-t�on (aer�al appl�cat�on), av�at�on combust�on tox�cology, postmortem av�at�on forens�c tox�cology, and cab�n a�r contam�nat�on. At the end of the references sect�on, further read�ngs are also suggested. Th�s art�cle �s ant�c�pated to be an �nformat�ve resource for subject matter assoc�ated w�th aerospace tox�cology.
2 AGRICULTURAL AVIATION
2.1 GeneralityUse of aer�al appl�cat�on �s �ncreas�ng throughout
the world to �ncrease food product�on. The appl�cat�on process �nvolves spray�ng of pest�c�des, herb�c�des, growth mod�fiers, fert�l�zers, and other agr�cultural chem�cals on crops. Many of these chem�cals are po�sonous to human be�ngs, caus�ng ser�ous s�gns/symptoms and poss�bly death (210). Inc�dents and acc�dents �nvolv�ng aer�al appl�cat�ons and handl�ng of commerc�al agr�cultural chem�cal preparat�ons (formulat�ons) do occur. Some examples are: (�) an exper�enced aer�al appl�cator p�lot, who acc�dentally sp�lled parath�on on h�s clothes wh�le pour�ng the concentrate from a 55-gallon drum 4 d earl�er and who afterwards became �rr�table and �ntroverted, was not feel�ng well and had a headache on the day he crashed h�s plane; (��) a p�lot, who was exposed to dr�ft-�ng parath�on and requ�red atrop�ne therapy, flew �nto a tree dur�ng pull-up; (���) an a�rcraft connector became loose after take-off and sprayed a m�xture conta�n�ng parath�on �n the p�lot’s face, saturat�ng h�s body w�th the spray, caus�ng h�m to lose control of the plane, wh�ch crashed; and (�v) a p�lot was splashed w�th a defol�ant dur�ng a fl�ght, wh�ch caused a crash, almost result�ng �n the p�lot’s death (191). Such acc�dental exposures and the development of aer�al dust allerg�es �n p�lots were top�cs of a group d�scuss�on on protect�ng agr�culture p�lots (191). In general, these agr�cultural chem�cals are tox�c (89, 109), and �f occupat�onal safety and precaut�onary measures are not properly taken, exposures of appl�cator personnel and agr�cultural a�rcraft acc�dent �nvest�gators to such chem�cals could lead to acute or chron�c po�son�ngs. Po�son�ngs of agr�cultural p�lots may, thus, contr�bute to av�at�on acc�dents, as well. These po�son�ngs could be the result of exposures to a s�ngle chem�cal or to mult�ple chem�cals (or chem�cal m�xtures).
2.2 Pesticidal ToxicologyTox�colog�cal aspects of organophosphorus and
organochlor�ne �nsect�c�des have been elaborated �n the l�terature (89, 168). Although not used anymore, d�chlorod�phenyltr�chloroethane (DDT) �s the most
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stud�ed organochlor�ne �nsect�c�de and has also served as a prototype for the tox�colog�cal propert�es of other organochlor�ne �nsect�c�des (89, 168). Organophos-phorus and organochlor�ne chem�cals adversely affect the funct�ons of the central nervous system. Behav�oral d�fficult�es have been �mpl�cated �n aer�al appl�cators fol-low�ng exposures to pest�c�des (100, 101, 171, 257, 299). S�gns/symptoms of anx�ety, uneas�ness, depress�on w�th weep�ng, d�zz�ness, emot�onal l�ab�l�ty, frequent and severe d�sagreement w�th fam�ly and coworkers, and be�ng unable to perform fam�l�ar tasks were reported dur�ng med�cal evaluat�ons of 2 agr�cultural p�lots act�vely engaged �n the aer�al appl�cat�on of organophosphorus/organochlor�ne �nsect�c�des, methyl parath�on, DDT, toxaphene, endr�n, and d�eldr�n (100, 101). Tox�colog�cal evaluat�on of post-mortem samples from p�lots k�lled wh�le engaged �n aer�al appl�cat�on revealed that blood chol�nesterase levels �n 44 of 104 p�lots (165) and 77 of 130 p�lots (166) were below the normal range, suggest�ng a problem of acute and/or chron�c tox�c�ty from organophosphorus pest�c�des appl�ed by agr�cultural a�rcraft. Reduced plasma chol�n-esterase levels were found �n 2 agr�culture p�lots �nvolved �n non-fatal av�at�on acc�dents (98, 99). Acc�dents and po�son�ngs �n aer�al appl�cat�ons have been documented (97-99). Aer�al appl�cat�on-related precaut�ons, s�gns and symptoms of pest�c�de po�son�ngs, and the�r treatments are summar�zed for protect�ng the agr�cultural p�lots (97, 191). These find�ngs suggested that better educat�onal efforts could reduce the acc�dents �n th�s sector of the agr�cultural act�v�ty.
For an aer�al spray�ng program to manage �nsect ep�-dem�cs �n large tracts of forest, extens�ve stud�es have been conducted of the tox�cology of �nsect�c�des (fen�troth�on and am�nocarb), the technology of aer�al spray�ng, the development of less hazardous formulat�ons, and the quant�tat�on of off-target dr�ft of aerosol�zed �nsect�c�des (108). These stud�es culm�nated �n �mprovements �n pest�c�de appl�cat�on and the establ�shment of regulat�ons on safety or buffer zones around human hab�tat�on for certa�n types of a�rcraft apply�ng d�fferent formulat�ons of the �nsect�c�des.
2.3 Multi-Agricultural Chemicals and Organic Solvents/Surfactants
There �s a potent�al for aer�al appl�cators, assoc�ated personnel, and a�rcraft acc�dent �nvest�gators to be exposed to mult�ple agr�cultural chem�cals and solvents/surfactants of the�r commerc�al preparat�ons for sprays, �f safety and precaut�onary measures were not properly taken. Such po�son�ngs could be attr�buted to the resultant of, and/or �nteract�ve effects of, each of the chem�cals and solvents/surfactants. Tox�c effects of m�xtures of parath�on (5 mg·kg−1), toxaphene (50 mg·kg−1), and/or d�chlorophen-
oxyacet�c ac�d (2,4-D; 50 mg·kg−1) for up to 7- and 14-d treatments �n m�ce were determ�ned to be the resultant of the effects exh�b�ted by the�r components �nd�v�dually (162). Metabol�c aspects of these 3 chem�cals suggest that the tox�c�ty of the parath�on plus toxaphene m�xture would be lower than that of parath�on, as toxaphene has the ab�l�ty to �ncrease the b�otransformat�on of parath�on, as well as of paraoxon, and the levels of al�esterase, thereby prov�d�ng a pool of non-cr�t�cal enzymes for the b�nd�ng of paraoxon (61). Because of these propert�es of toxaphene, �t �s ant�c�pated that the tox�c�ty of the parath�on plus toxaphene plus 2,4-D m�xture would also be lower than that of parath�on (61). Chron�c stud�es on the m�xtures of 3 herb�c�des—alachlor, atraz�ne, and/or p�cloram—�n m�ce suggest that the m�xtures may cause hepatotox�c�ty and st�mulate the l�ver xenob�ot�c-metabol�z�ng enzymes (51). A chron�c tox�colog�cal evaluat�on of m�xtures of 10 w�dely used pest�c�des—alachlor, aldr�n, atraz�ne, 2,4-D, DDT, d�eldr�n, endosulfan, l�ndane, parath�on, and toxaphene—�n m�ce revealed that these m�xtures �nduce the xenob�ot�c-metabol�z�ng enzymes �n l�ver. Therefore, exposures to the pest�c�dal m�xtures m�ght cause deleter�ous effects �n other spec�es, �nclud�ng humans, by enhanc�ng the metabol�sm of xenob�ot�cs (52). In mult�-chem�cal exposures, �nteract�ve effects among those chem�cals play a contr�butory role towards assoc�ated po�son�ngs. Th�s type of po�son�ng could be exempl�fied �n a mult�-chem�cal death �nvolv�ng caffe�ne, n�cot�ne, and malath�on (62) and �n a death attr�buted to �ngest�on of malath�on �nsect spray (66). In the later case, �n v�tro �nh�b�t�on of chol�nesterases and presence of xylenes and other volat�les �n certa�n postmortem samples were demonstrated (66). Therefore, these organ�c solvents may not only �nteract w�th other m�xture-chem�cals, but may also exh�b�t the�r own tox�c effects. Ethylbenzene, a major component of m�xed xylenes used as solvents �n agr�culture �nsect�c�de sprays, has been found to �ncrease �nc�dences of renal tubule, alveolar/bronch�olar, and he-patocellular neoplasms and of test�cular and renal tubule adenomas �n rats (278). Increased �nc�dences of renal tubule hyperplas�a, of alveolar ep�thel�al metaplas�a, and of severe nephropathy have been reported �n rats exposed to ethylbenzene. The herb�c�de glyphosate, though �t does not b�oaccumulate, b�omagn�fy, or pers�st �n a b�olog�-cally ava�lable form �n the env�ronment and �s nontox�c to an�mals, may be formulated w�th surfactants (261). Such formulat�ons �ncrease the efficacy of the herb�c�de but, �n some cases, are more tox�c to aquat�c organ�sms than the parent mater�al. Some r�sks were observed for measured concentrat�ons of glyphosate �n surface waters result�ng from aer�al appl�cat�on of a formulat�on equ�va-lent to Roundup to forestry areas �n Canada.
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2.4 Application SafetyAv�at�on author�t�es have been concerned about the
tox�c effects of agr�cultural chem�cals on agr�culture p�lots. In the former Sov�et Un�on, aer�al appl�cators are requ�red to ma�nta�n records of the chem�cals used for crop spray�ng and �ts durat�on (89). In the Un�ted States, tox�colog�cal problems �n aer�al appl�cat�on were recogn�zed �n early 1960s, and a cons�derable amount of appl�ed stud�es were conducted at the U.S. Department of Transportat�on Federal Av�at�on Adm�n�strat�on’s (FAA’s) C�v�l Aerospace Med�cal Inst�tute (CAMI) �n Oklahoma C�ty, OK, to enhance the safety of agr�cultural p�lots and the�r support personnel. The stud�es conducted at CAMI are summar�zed �n Table I.
2.5 Exposure MonitoringThe health r�sk of aer�al spray�ng �s well known for
p�lots and ground ma�ntenance workers. Therefore, such agr�cultural workers �n the aer�al spray�ng �ndustry must be placed on occupat�onal surve�llance programs des�gned to detect the earl�est tox�c exposures to these chem�cals. S�nce organophosphorus compounds and carbamates �nh�b�t acetylchol�nesterase and chol�nesterases, act�v�t�es of these enzymes �n red blood cells, plasma, or whole blood (30–50% �nh�b�t�on) �s measured for mon�tor�ng exposures to these �nsect�c�des (89, 128, 168). Examples of tentat�ve max�mum perm�ss�ble concentrat�ons of parent compounds and/or the�r metabol�tes are: (�) 0.5 mg of p-n�trophenol per g of creat�n�ne �n ur�ne for parath�on and 10 mg of naphthol per g of creat�n�ne �n ur�ne for carbaryl; (��) 15 µg of d�eldr�n per 100 mL of blood, 2 µg of l�ndane per 100 mL of blood, and 5 µg of endr�n per 100 mL of blood; (���) 30 µg of hexachlorobenzene per 100 mL of blood and/or presence of 2,4,5-tr�chloro-phenol �n ur�ne; (�v) 0.05 mg of pentachlorophenol per 100 mL of plasma and/or 1 mg of pentachlorophenol per g of creat�n�ne �n ur�ne; and (v) detect�on of 2,4-D and 2,3,5-tr�chlorophenoxyacet�c ac�d �n ur�ne (168).
3 AVIATION COMBUSTION TOXICOLOGY
3.1 Combustion, Fire, and SmokeCombust�on �s a rap�d exotherm�c chem�cal cha�n
react�on between a fuel and oxygen (a�r) (167, 189, 259, 264). Heat, fuel, oxygen, and chem�cal react�on are neces-sary components for the development of a fire. F�re �s a complex, dynam�c, and phys�cochem�cal process and �s the result of a rap�d chem�cal react�on generat�ng smoke, heat, flame, and l�ght. Smoke cons�sts of part�culate mat-ters, as well as a var�ety of �nv�s�ble combust�on gases and vapors suspended �n the fire atmosphere. In other words, smoke �s a collo�dal solut�on cons�st�ng of gases, volat�les,
sem�-volat�les, water vapors and droplets, sol�d part�cles, and �rr�tants. The �nvolvement of part�cles and �rr�tants �n obscur�ng v�s�on and �n caus�ng eye �rr�tat�on, �nclud�ng resp�ratory �rr�tat�on, cannot be �gnored. Thus, combus-t�on of burnable mater�als generates var�ous products �n smoke and �t may d�m�n�sh l�ght and obscure v�s�on, and �ts gases could be tox�c (53, 63, 64, 236).
Uncontrolled fires threaten res�dent�al and commerc�al structures and transportat�on systems, �nclud�ng aerospace travel. Modern a�rcraft benefit from fire retardants and fire ext�ngu�sh�ng systems to such an extent that �n-fl�ght fires are rare. However, surv�vable crashes followed by fire do occur, pr�mar�ly from fuel sp�lls around the a�rcraft. Although the cab�n occupants may surv�ve the �n�t�al forces of such crashes, they are frequently unable to es-cape from the fire env�ronment because of performance �mpa�rment from smoke-caused tox�c�ty (236). Post-crash fire �s cons�dered to be the most �mportant determ�nant of p�lot fatal�t�es �n commuter a�rcraft/a�r tax� crashes (177). Accord�ng to a study by the Internat�onal Cab�n Water Spray Research Management Group, there were 95 fire-related c�v�l passenger a�rcraft acc�dents world-w�de over a 26-yr per�od (32). F�re cla�med approx�mately 2,400 l�ves �n those acc�dents. A U.S. General Account�ng Office publ�cat�on reveals that 32 (approx�mately 16%) U.S. transport a�rcraft acc�dents between 1985 and 1991 �nvolved fire, and 140 (22%) fatal�t�es �n these acc�dents resulted from the effects of fire and smoke (126). Dur�ng 1991–1998, postmortem samples from 3,857 fatal�t�es of 2,837 av�at�on acc�dents were rece�ved by CAMI for tox�colog�cal evaluat�on. Of these acc�dents, 1,012—en-compass�ng 1,571 (41%) fatal�t�es—were fire assoc�ated (67, 68). The deaths of the 3 Apollo 1 crewmembers �n the 1967 fire acc�dent was due to the�r exposure to tox�c combust�on products (276), and the �nvolvement of fire has been documented �n the 23 February 1997 acc�dent on the M�r aerospace stat�on (289). In th�s aerospace ac-c�dent, the fire burned for approx�mately 90 s. The crew was exposed to heavy smoke for 5 to 7 m�n and donned the�r masks �n response. Subsequent med�cal exam�nat�on revealed that all crewmembers were �n good health.
3.2 Smoke Gases and ToxicityDepend�ng upon the chem�cal character�st�cs of
burn�ng mater�als and env�ronmental cond�t�ons, such as temperature and oxygen content, the amounts of smoke products, gases, and other volat�les generated var�es from fire to fire (123, 212). Every fire �s d�fferent. Smoke compos�t�on and �ts tox�c�ty can change drast�-cally when d�fferent mater�als are present �n a combust�on env�ronment and can be further altered by the presence of fire retardants and p�gments. A mater�al burned under one cond�t�on could be nontox�c, but �t could be tox�c
4
Tabl
e I.
Sum
mar
izat
ion
of A
eria
l App
licat
ion-
Rel
ated
Stu
dies
Con
duct
ed a
t CA
MI
Age
nt(s
) or T
opic
Su
mm
ary
Ref
eren
ce
Lind
ane
and
diel
drin
A
ltera
tions
in se
vera
l bio
chem
ical
val
ues o
f rat
tiss
ues b
y ch
roni
c ex
posu
res t
o lin
dane
an
d ch
ange
s in
the
upta
ke o
f L-m
ethi
onin
e by
chi
ck h
eart
and
liver
cel
ls b
y ch
roni
c ex
posu
re to
die
ldrin
Dau
gher
ty e
t al.
(93)
Ana
lysi
s of h
azar
ds in
the
aeria
l ap
plic
atio
n
Dis
cuss
ion
on th
e na
ture
of t
he c
hem
ical
s, th
e sy
mpt
oms o
f tox
icity
, rec
omm
ende
d tre
atm
ent,
and
sugg
estio
ns fo
r saf
e-ha
ndlin
g of
toxi
c pe
st-c
ontro
l che
mic
als
Smith
(254
)
Car
diov
ascu
lar e
ffec
ts o
f end
rin
Cau
satio
n of
bra
dyca
rdia
, hyp
erte
nsio
n, sa
livat
ion,
hyp
er-e
xcita
bilit
y, to
nic-
clon
ic
conv
ulsi
ons,
incr
ease
d bo
dy te
mpe
ratu
re, l
euko
cyto
sis,
and
decr
ease
d bl
ood
pH b
y en
drin
, app
eare
d to
be
caus
ed b
y di
rect
act
ion
on th
e ce
ntra
l ner
vous
syst
em
Emer
son
et a
l. (1
11)
Die
ldrin
, lin
dane
, hep
tach
lor,
isod
rin, a
nd
endr
inR
educ
tion
in th
e es
terif
icat
ion
of in
orga
nic
phos
phat
e by
50%
, with
out a
ffec
ting
lact
ic
acid
pro
duct
ion
in c
hick
ens a
nd ra
ts e
xpos
ed to
die
ldrin
, but
no
such
redu
ctio
n in
es
terif
icat
ion
by o
ther
chl
orin
ated
pes
ticid
es li
ndan
e, h
epta
chlo
r, is
odrin
, and
end
rin
Dau
gher
tyet
al.
(94)
Cas
es in
volv
ing
aeria
l app
licat
ion
of
orga
noph
osph
orus
inse
ctic
ides
Si
gns/
sym
ptom
s of a
nxie
ty, u
neas
ines
s, de
pres
sion
, wee
ping
, diz
zine
ss, e
mot
iona
l lia
bilit
y, d
isag
reem
ent w
ith fa
mily
/cow
orke
rs, a
nd u
nabl
e to
per
form
fam
iliar
task
s D
ille
and
Smith
(100
)
Chr
onic
and
acu
te e
ffec
ts o
f end
rin o
n re
nal f
unct
ion
Syst
emic
hyp
erte
nsio
n an
d in
crea
sed
rena
l vas
cula
r res
ista
nce
in d
ogs b
y ac
ute
expo
sure
to e
ndrin
, attr
ibut
ed to
a sy
mpa
tho-
adre
nal a
ctio
n
Dev
elop
men
t of p
rogr
essi
ve sy
stem
ic h
ypot
ensi
on w
ith v
aria
ble
chan
ges i
n re
nal
func
tion
and
term
inal
rena
l vas
odila
tatio
n in
dog
s chr
onic
ally
exp
osed
to e
ndrin
Not
e: T
hese
find
ings
wer
e re
late
d to
hem
odyn
amic
alte
ratio
ns in
the
perip
hera
l va
scul
atur
e. N
o ev
iden
ce o
f ren
al fa
ilure
was
obs
erve
d du
e to
chr
onic
inse
ctic
ide
pois
onin
g.
Rei
ns e
t al.
(223
)
Path
olog
ical
eff
ects
of e
ndrin
and
die
ldrin
M
ore
seve
re e
ffec
ts o
f die
ldrin
on
the
cold
-ada
pted
rats
than
on
the
room
-tem
pera
ture
ra
tsC
lark
(72)
Effe
cts o
f end
rin a
nd c
arbo
n te
trach
lorid
e R
ever
sibl
e in
crea
se in
hep
atic
fat c
onte
nts o
f rat
s tre
ated
with
end
rin a
nd c
arbo
n te
trach
lorid
e
Cla
rk (7
1)
Effe
cts o
f end
rin o
n re
nal f
unct
ion
and
hem
odyn
amic
s, pe
riphe
ral v
ascu
lar
syst
em, v
enou
s ret
urn
and
cate
chol
amin
e re
leas
e, a
nd th
e ca
rdio
vasc
ular
syst
em
Expl
orat
ion
of th
e ef
fect
s of e
ndrin
in d
ogs o
n re
nal f
unct
ion
and
hem
odyn
amic
s, pe
riphe
ral v
ascu
lar s
yste
m, v
enou
s ret
urn
and
cate
chol
amin
e re
leas
e, a
nd th
e ca
rdio
vasc
ular
syst
em; a
nd e
luci
datio
n of
the
mec
hani
sms o
f end
rin-in
duce
d he
moc
once
ntra
tion
Hin
shaw
et a
l.(1
44)
Expo
sure
of p
arat
hion
and
dev
elop
men
t of
alle
rgy
tow
ards
aer
ial d
usts
G
roup
dis
cuss
ion
on p
rote
ctin
g ag
ricul
ture
pilo
ts
Moh
ler a
nd H
arpe
r (1
91)
Hum
an fa
ctor
s in
gene
ral a
viat
ion
acci
dent
sD
iscu
ssio
n on
the
role
of m
edic
al c
ondi
tions
and
pes
ticid
es in
avi
atio
n ac
cide
nts
Dill
e an
d M
orris
(98,
99
)
5
Cho
lines
tera
se m
easu
rem
ent
Dev
elop
men
t of a
n au
tom
ated
met
hod
for m
easu
ring
chol
ines
tera
se a
ctiv
ity in
blo
od
and
tissu
es o
f ani
mal
s poi
sone
d w
ith o
rgan
opho
spha
tes a
nd c
arba
mat
es
Fow
ler a
nd
McK
enzi
e (1
20)
Dru
g an
d to
xic
haza
rds i
n ge
nera
l av
iatio
n Su
mm
ary
of a
eria
l app
licat
ion
rela
ted
prec
autio
ns, s
igns
and
sym
ptom
s of p
estic
ide
pois
onin
g, a
nd th
eir t
reat
men
ts
Dill
ie a
nd M
ohle
r (9
7)
Effe
cts o
f dis
ulfo
ton
In
crea
se in
per
form
ance
in ra
ts g
iven
dis
ulfo
ton
at 1
0, 2
5, a
nd 5
0 pp
m in
die
t and
w
ater
ad
libitu
man
d in
hibi
tion
of b
rain
ace
tylc
holin
este
rase
by
mor
e th
an 7
5% o
f no
rmal
in th
e m
ost s
ever
ely
expo
sed
grou
p
Pear
son
et a
l.(2
11)
Hum
an b
lood
cho
lines
tera
se
Dec
reas
e of
onl
y 10
% o
f the
orig
inal
cho
lines
tera
se a
ctiv
ity u
pon
stor
age
of re
d ce
ll he
mol
ysat
es fo
r les
s tha
n 12
h a
t roo
m te
mpe
ratu
re, u
p to
3 d
at 4
°C, a
nd u
p to
6 w
k at
–2
0°C
Not
e: W
hole
blo
od h
emol
ysat
es a
nd p
lasm
a m
ay b
e st
ored
for 6
d a
t roo
m te
mpe
ratu
re
and
6 w
k, if
refr
iger
ated
or f
roze
n.
Cra
ne e
t al.
(78)
Cho
lines
tera
se m
etho
ds
Com
paris
on o
f 3 c
holin
este
rase
met
hods
Impo
rtanc
e of
cho
lines
tera
se te
sts i
n ap
plic
ator
s prio
r to
the
aeria
l app
licat
ion
seas
on
Cra
ne e
t al.
(77)
Effe
cts o
f end
rin o
n br
ain
Bra
in b
ioel
ectri
c ph
enom
ena
caus
ed b
y en
drin
at d
oses
wel
l bel
ow th
ose
caus
ing
seiz
ures
or o
ther
gro
ss b
ehav
iora
l cha
nges
Seiz
ures
in sq
uirr
el m
onke
ys b
y ch
roni
c ad
min
istra
tion
of th
is p
estic
ide
Reo
ccur
renc
e of
seiz
ures
som
e m
onth
s afte
r the
term
inat
ion
of e
ndrin
adm
inis
tratio
n,
unde
r stre
ssfu
l con
ditio
ns, s
ugge
stin
g th
at th
is p
heno
men
on m
ay h
ave
been
cau
sed
by
a st
ress
-indu
ced
rele
ase
of e
ndrin
from
adi
pose
tiss
ue st
orag
e si
tes
Dis
cuss
ion
on so
me
impl
icat
ions
of t
hese
find
ings
for a
eria
l app
licat
ors
Rev
zin
(225
)
Dis
ulfo
ton
Adv
erse
eff
ects
on
the
repr
oduc
tion
syst
em in
rats
by
disu
lfoto
n
Not
e: T
he n
umbe
r of p
regn
anci
es w
as d
ecre
ased
in th
e an
imal
s rec
eivi
ng th
is
pest
icid
e. S
uch
decr
ease
cou
ld h
ave
been
attr
ibut
ed to
such
fact
ors a
s alte
ratio
n in
the
estru
s cyc
les,
the
rece
ptiv
ity o
f the
fem
ale
anim
als,
and
decr
ease
in sp
erm
co
ncen
tratio
n or
via
bilit
y.
Rya
net
al.
(231
)
Seru
m o
r pla
sma
chol
ines
tera
se m
etho
ds
Eval
uatio
n of
4 se
rum
or p
lasm
a ch
olin
este
rase
met
hods
and
rela
tions
hips
for i
nter
-co
nver
sion
am
ong
thei
r res
pect
ive
units
Emph
asis
on
the
impo
rtanc
e of
the
chol
ines
tera
se te
st in
app
licat
ors p
rior t
o th
e ae
rial
appl
icat
ion
seas
on
Cra
ne e
t al.
(79)
Tabl
e I (
cont
inue
d)
6
Effe
cts o
n pe
rfor
man
ce o
f pig
eons
and
m
onke
ys o
f pho
sdrin
(mev
inph
os),
a ch
olin
este
rase
inhi
bito
r
A d
ose
rela
ted
decr
ease
in re
spon
se ra
te w
ith th
e an
imal
s and
dec
rem
ents
in b
ehav
ior
at d
oses
bel
ow w
hich
ext
erna
l sym
ptom
s of p
hosd
rin p
oiso
ning
occ
urre
d Le
wis
et a
l. (1
71)
Mev
inph
os (p
hosd
rin)
Inhi
bitio
n of
the
ampl
itude
of h
ippo
cam
pal-e
voke
d po
tent
ials
in sq
uirr
el m
onke
ys b
y m
evin
phos
(pho
sdrin
) in
the
dose
rang
e of
0.0
5–0.
2 m
g·kg
1 , with
no
perip
hera
l sig
ns
of p
oiso
ning
such
as t
rem
or a
nd sa
livat
ion
Emph
asis
that
mev
inph
os p
rodu
ces c
hang
es in
bra
in fu
nctio
n in
the
abse
nce
of th
e pe
riphe
ral s
ympt
omat
olog
y us
ually
take
n as
indi
cato
rs o
f poi
soni
ng b
y ae
rial
appl
icat
or p
erso
nnel
Con
clus
ion
that
exp
osur
e to
mev
inph
os m
ay b
e un
expe
cted
ly h
azar
dous
sinc
e th
e ae
rial a
pplic
ator
s may
be
unaw
are
that
they
hav
e be
en p
oiso
ned
Rev
zin
(226
)
Mev
inph
os p
oiso
ning
with
atro
pine
B
ased
upo
n sq
uirr
el m
onke
y ex
perim
ents
, pot
entia
lly h
azar
dous
dys
func
tions
of v
isua
l pe
rcep
tion
in a
eria
l app
licat
or p
erso
nnel
bei
ng tr
eate
d fo
r mev
inph
os p
oiso
ning
with
at
ropi
ne
Rev
zin
(227
)
Toxi
colo
gica
l fin
ding
s in
fata
l civ
il av
iatio
n ac
cide
nts (
1968
–197
4)
Blo
od c
holin
este
rase
act
ivity
bel
ow th
e lo
wer
lim
it of
the
norm
al ra
nge
in 4
4 of
the
104
aeria
l app
licat
or p
ilots
La
cefie
ldet
al.
(165
)
Chl
ordi
mef
orm
Li
ttle
or n
o ex
tra ri
sk in
aer
ial a
pplic
ator
s (or
oth
ers)
shou
ld th
ey b
e ta
king
p-
chlo
roph
enyl
alan
ine,
DL-
-met
hyl-p
-tyro
sine
, phe
ntol
amin
e, m
ethy
serg
ide,
and
ph
enyl
ephr
ine
durin
g po
tent
ial e
xpos
ure
to c
hlor
dim
efor
m
Smith
et a
l. (2
56)
Toxi
colo
gica
l eva
luat
ion
of p
ostm
orte
m
sam
ples
from
174
pilo
ts k
illed
in a
eria
l ap
plic
atio
n ac
cide
nts
Inci
denc
e of
alc
ohol
in sp
ecim
ens s
imila
r for
agr
icul
ture
pilo
ts a
nd o
ther
gen
eral
av
iatio
n pi
lots
, but
the
alco
hol b
lood
leve
ls te
nded
to b
e lo
wer
in th
e fo
rmer
cat
egor
y of
pilo
ts
Evid
ence
of t
he u
se o
f dru
gs o
r med
icat
ions
less
in a
gric
ultu
re p
ilots
than
in o
ther
ge
nera
l avi
atio
n pi
lots
Cho
lines
tera
se le
vels
bel
ow n
orm
al in
the
agric
ultu
re p
ilots
, sug
gest
ing
a co
ntin
uing
pr
oble
m o
f acu
te a
nd/o
r chr
onic
toxi
city
from
pes
ticid
es a
pplie
d by
agr
icul
tura
l ai
rcra
ft
Lace
field
et a
l. (1
66)
Tabl
e I (
cont
inue
d)
7
when burned under a d�fferent cond�t�on (86, 123)—for example, cotton upon burn�ng under low-oxygen smol-der�ng cond�t�ons produces pr�mar�ly carbon monox�de (CO) but the much less tox�c carbon d�ox�de (CO
2) under
flam�ng cond�t�ons. Nylons tend to break down �nto the�r relat�vely nontox�c monomers at low temperatures and produce tox�c hydrogen cyan�de (HCN) when flam�ng. F�re retardants decrease flammab�l�ty, but they may also enhance smoke tox�c�ty (123, 212). Smoke tox�c�ty of a fire retardant-treated polymer was found to be cons�der-ably h�gher than that of the non-treated polymer, as �t was determ�ned that the smoke conta�ned a very tox�c b�cycl�c phosphate (212). Most cab�n furn�sh�ngs conta�n carbon and w�ll produce CO when burned, but s�lk, wool, and many n�trogen-conta�n�ng synthet�cs are common sources of HCN �n fires (123). Carbon-conta�n�ng mater�-als generate CO, and n�trogen-conta�n�ng mater�als also generate HCN (53, 64, 113, 123, 138, 244). Benzene vapors and aromat�c�ty-assoc�ated black soot would be produced from the burn�ng of phenyl group-conta�n�ng polymers, whereas hydrogen chlor�de from chlor�ne- conta�n�ng polymers (Table II). Irr�tants, hydrogen chlor�de and acrole�n (CH
2CHCHO), can be produced
from burn�ng w�r�ng �nsulat�on and some other cab�n mater�als (76, 83, 123). Hydrogen fluor�de, hydrogen sulfide, sulfur d�ox�de, and n�trogen d�ox�de gases have also been reported to be present �n smoke (112, 113, 142). Format�on of these gases �s assoc�ated w�th a�rcraft mater�al formulat�ons conta�n�ng halogens, cyan�de, sul-fur, and n�trogen mo�et�es. Smoke �nhalat�on can cause d�zz�ness and confus�on, can �nduce �rr�tat�on, tears, pa�n, and d�sor�entat�on, and can produce �ncapac�tat�on and death. It can also cause delayed tox�colog�cal/patholog�cal effects, wh�ch could be revers�ble or �rrevers�ble.
Oxygen, CO2, and CO can eas�ly be analyzed �n a
smoke env�ronment sample by gas chromatography, but the ac�d gases, l�ke hydrogen cyan�de and hydrogen chlo-r�de, are not so eas�ly analyzable. The�r analyses requ�re add�t�onal steps and precaut�ons because of the�r h�gh water solub�l�ty. Therefore, they are analyzed as the�r respect�ve an�ons, for example, cyan�de and chlor�de. Because of �ncomplete ox�dat�on, organ�c compounds are also present �n smoke. Those compounds can be analyzed by trapp�ng the smoke �n var�ous solvents (water, aceton�-tr�le, and chloroform) or �n carbon traps. These trapped organ�c compounds can subsequently be analyzed by gas chromatography/mass spectrometry, by h�gh performance l�qu�d chromatography/mass spectrometry, and/or by gas chromatography w�th a Four�er transform �nfrared or atom�c em�ss�on detector. Some of these compounds can be character�zed and confirmed �f they are common compounds or �f the�r reference standards are commerc�ally ava�lable. Otherw�se, the�r chem�cal structures can only be eluc�dated by soph�st�cated, analyt�cal techn�ques. Some of the smoke compounds cannot be character�zed. Th�s l�m�tat�on �s due to the very fact that free rad�cal chem�cal react�ons are �nvolved �n the combust�on process; thus, �t becomes d�fficult to pred�ct the end products. Th�s d�f-ficulty becomes more prevalent when burn�ng cond�t�ons change—for example, between smolder�ng and complete burn�ng—and when fire retardants, preservat�ves, and/or stab�l�zers are present �n the mater�al be�ng evaluated. Phosphorus present �n synthet�c mater�als may add an extra var�able. Because of the analyt�cal l�m�tat�ons and the unknown tox�c�ty of all the compounds �n smoke, an�mal models have been used to determ�ne �ts overall total tox�c�ty. Th�s approach �ntegrates poss�ble �nterac-t�ons among the smoke components and �s able to dem-onstrate the net tox�c�ty of all components. Otherw�se,
Table II. Combustion Gases From Polymersa
Polymers Chemical Unit Constituent Combustion Gases
Polyethylene (–CH2CH2–)n CO, CO2
Nylon 6/6 [–NH(CH2)6NHCO(CH2)4CO–]n CO, HCN, CO2
Polyamide [–NH(CH2)nNHCO(CH2)nCO–]n CO, HCN, CO2
Polystyrene [–CH2CH(C6H5)–]n CO, C6H6b, CO2
Chlorinated polyethylene (–CH2CH2–)n; (Cl = 40%) CO, HClb, CO2
Polysulfone [–C6H4–4–C(CH3)2C6H4–4–OC6H4–4–SO2C6H4–4–O–]n CO, SO2b, CO2
aSanders et al. (243, 244); Fenner (119); Harper (135). bBenzene (C6H6); Hydrogen chloride (HCl); Sulphur dioxide (SO2).
8
the�r contr�but�ons to the overall tox�c�ty could not be evaluated. Although structures of compounds can cur-rently be eluc�dated by modern soph�st�cated chem�cal and analyt�cal techn�ques, an an�mal model �s st�ll an excellent and val�d sc�ent�fic approach to �ntegrate the overall tox�c�ty of smoke.
3.3 Aircraft Material TestingThe presence of cyan�de �n blood spec�mens of the
v�ct�ms of the 1970 Cap�tol Internat�onal A�rways DC-8 post-crash fire acc�dent at Anchorage, AK, necess�tated the research �nto the or�g�n of cyan�de �n a�rcraft fires (204, 235). At that t�me, not much was known about the potent�al for a�rcraft �nter�or mater�als to produce tox�c combust�on gases, even about the tox�c�ty of �nd�v�dual combust�on gases. Us�ng a small-an�mal test system, 75 a�rcraft �nter�or mater�als—panels, panel components, foams, fabr�cs, coated fabr�cs, floor�ngs, thermoplast�cs, cargo l�ners, transparenc�es, �nsulat�ons, and elastomers—were ranked for the�r tox�c�ty based upon the relat�ve t�me-to-�ncapac�tat�on (t
�)
and t�me-to-death (t
d) caused
by the �nhalat�on of thermal degradat�on of the �nter�or mater�als �n rats (88). The former �s a real�st�c parameter for est�mat�ng escape t�me from fire env�ronments, and the latter �s a parameter for find�ng out delayed adverse effects after exposure to smoke. These 75 polymer�c ma-ter�als were thermally decomposed us�ng an �sothermal heat�ng reg�men at 600oC, though the decompos�t�on method may not necessar�ly represent the actual processes occurr�ng �n a “true” fire. Tox�c potent�als of 14 �nsulat�ng mater�als �n rats w�th respect to response t�mes were tested under 3 burn�ng cond�t�ons (76). These cond�t�ons were low-temperature, non-flam�ng; low-temperature flam�ng w�th hot-w�re �gn�t�on; and h�gh-temperature, flam�ng at 750oC, w�th or w�thout �gn�t�on. Naturally, there were d�fferences �n response t�mes at d�fferent combust�on cond�t�ons. Based upon the find�ngs, �t was proposed that mater�als should be tested at several cond�t�ons, and they should be ranked based upon the most tox�c-response t�me observed.
Relat�ve tox�c�ty of 2 a�rcraft seat fire-block�ng layer mater�als (Norfab and Vonar), des�gned to delay the �nvolvement of thermally sens�t�ve polyurethane foam seat cush�ons �n an a�rcraft fire, was establ�shed for the�r gaseous combust�on products (239). Each mater�al was thermally decomposed under 5 thermal env�ronments—2 contact temperatures (600oC and 750oC) �n a hor�zon-tal hot tube furnace and 3 flux levels (2.5, 5.0, and 7.5 W·cm−2) �n a rad�ant heat furnace. Rats were exposed to the produced combust�on products �n an an�mal exposure chamber w�th a cage, and the tox�colog�cal end po�nt (t
�)
was recorded when the rats could no longer perform the coord�nated act of walk�ng �n the rotat�ng cage (when
sl�d�ng or tumbl�ng began). In 3 of the 5 test env�ron-ments, the gaseous products of Norfab (an alum�n�zed synthet�c fabr�c) produced shorter t
�s than those by the
products of Vonar (a neoprene foam product). HCN was detected �n the combust�on products of Norfab but not �n the combust�on products of Vonar. The greater apparent tox�c�ty of Norfab was poss�bly because of HCN. Add�t�onal stud�es that ranked 9 flat panel mater�als based upon the�r combust�on products �n rats suggested that only the h�gher temperatures �n both the combust�on tube and rad�ant heat systems proved to be su�table for tox�colog�cal d�fferent�at�on between the panels. The shortest t
�s occurred at the h�ghest temperature/heat flux
cond�t�on for both chambers (86). A comparat�ve tox�c�ty study �nvolv�ng rank�ngs of 6 polymer�c a�rcraft cab�n mater�als—polyam�de (I), polystyrene (II), Nylon 6/6 (III), polysulfone (IV), polyethylene (V), and chlor�nated polyethylene (VI)—was conducted �n rats (243, 244). An�mals were exposed to the pyrolys�s products from selected we�ghts of each polymer for 30 m�n �n a 265-L combust�on/exposure system. The LC
50s were determ�ned
follow�ng a 14-d observat�on per�od. The t�s were also
measured at 16 g (60 mg·l−1) and at the�r respect�ve LC50
s us�ng the �nab�l�ty of rats to walk �n rotat�ng cages as a cr�ter�on for �ncapac�tat�on. The LC
50s (mg·l−1) of the
polymers had the order of I (45.7) < II (56.6) ≈ III (58.1) < IV (63.2) < V (75.5) < VI (87.5), wh�le the�r t
�s (m�n)
at 16 g (60 mg·l−1) had the order of III (6.6) ≈ I (7.3) < V (11.7) ≈ II (12.0) < VI (18.4) < IV (21.1). Based on the t
�s at LC
50s, the polymers were grouped �nto III and
V (10.5, 11.0); I, II, and VI (14.1-15.0); and IV (19.5). These 2 endpo�nts d�d not exh�b�t the same relat�ve tox�c hazard rank�ngs for these polymers. Also, t
�s were not
equal at the LC50
concentrat�ons, a cond�t�on of equal lethal�ty, demonstrat�ng the poss�ble �nvolvement of d�f-ferent mechan�sms of act�on for the combust�on products of these polymers at the selected end po�nts. In sp�te of exper�mental l�m�tat�ons, tox�c�ty rank�ng of a�rcraft mater�als has appl�cab�l�ty �n m�n�m�z�ng the tox�c�ty of smoke and the spread�ng of fires.
3.4 Gases and Their Interactive Effects3.4.1 Gas Interactions
S�nce a�rcraft mater�als, upon combust�on, have the potent�al for generat�ng hydrogen hal�des (hydrogen fluor�de and hydrogen chlor�de), HCN, and n�trogen d�ox�de (142), exper�ments were conducted w�th rats to determ�ne tox�c effects (lethal�ty) of short-term exposures to these gases. These exper�ments were conducted both w�th s�ngle gases and �n comb�nat�on w�th CO. These stud�es show the tox�c�ty rank�ngs of the 4 products to be HCN > n�trogen d�ox�de > hydrogen fluor�de > hydrogen chlor�de. CO concentrat�ons, wh�ch alone are not hazard-
9
ous, do not enhance the tox�c response to these gases. Effects of hydrogen chlor�de �nhalat�on have been stud�ed on t
� and t
d �n rats (85). These 2 endpo�nts were equated
to the atmospher�c hydrogen chlor�de concentrat�on by stat�st�cally der�ved regress�on equat�ons, and the poss�ble relat�onsh�p was d�scussed between the effect�ve tox�c doses of th�s gas for rats and those reported for humans. Tox�colog�cal evaluat�on of another �rr�tant acrole�n—a combust�on product of certa�n mater�als used �n a�rcraft �nter�ors—�n rats �nd�cated that concentrat�ons requ�red to produce �ncapac�tat�on were 100 t�mes greater than those suggested by the sc�ent�fic l�terature; equat�ons were der�ved to allow pred�ct�on of t
� and t
d for the laboratory
rat (87). The poss�ble relat�onsh�p between the effect�ve tox�c doses of acrole�n for rats, and those reported for humans, was also d�scussed.
Influence of elevated temperatures—amb�ent versus elevated temperatures from 40 to 60°C—on the effects of CO-�nduced t
�s �n rats were stud�ed as a funct�on of
CO concentrat�on and/or temperature �n an exposure chamber (240-242). The comb�ned CO plus elevated temperature exposures and exposures to CO and elevated temperatures (40–60oC) alone �nd�cated that �ncapac�ta-t�on occurred earl�er when CO �nhalat�on was comb�ned w�th a whole-body, elevated temperature env�ronment than that was observed for the same exposure parameters appl�ed �nd�v�dually. An emp�r�cal equat�on was der�ved that allows calculat�ng a pred�cted t
� for comb�nat�ons of
CO and temperature.Further �nteract�ve stud�es on CO and acrole�n by
exposures of rats to exper�mental atmospheres of CO �n a�r, acrole�n �n a�r, and m�xtures of CO and acrole�n �n a�r and the measurement of t
� �nd�cated no ev�dence of
synerg�st�c act�on, s�nce the effect of the comb�nat�on was never greater than that pred�cted by the sum of the 2 �nd�v�dual gas effects (81, 82). However, ev�dence d�d ex�st for an �nh�b�tory or antagon�st�c effect of an undefined mechan�sm when acrole�n was present �n the m�xture at concentrat�ons of lesser tox�c potency than that of CO. Equat�ons were der�ved that allows the calculat�on of a pred�cted t
� for comb�nat�ons of CO and acrole�n
concentrat�ons. Evaluat�on of the tox�c potenc�es of CO, HCN, and
the�r m�xtures by the measurement of t� �n rats as a func-
t�on of gas concentrat�ons �nd�cated that the 2 gases are fract�onally add�t�ve (80), w�th no �nd�cat�on of syner-g�sm—where�n the effect of the comb�nat�on would have been greater than that pred�cted from the sum of the 2 �nd�v�dual effects. Regress�on equat�ons were der�ved that descr�be those relat�onsh�ps for exposure to CO or HCN alone. An emp�r�cal equat�on was der�ved that allows calculat�on of the pred�cted t
� for any comb�nat�on of CO
and HCN concentrat�ons. A dose-response model�ng,
based upon the concept of “Fract�onal Effect�ve Dose” (see next sect�on), was used to dev�se a mathemat�cal model for est�mat�ng t
� produced by defined m�xtures
of CO and HCN.
3.4.2 Fractional Effective Dose (FED)The average concentrat�on of a gas to wh�ch an an�mal
was exposed �s calculated from the area under the gas concentrat�on (C)-exposure t�me (t) curve �ntegrated from t = 0 to t = t
i, represent�ng the C∙t
i product (80). The C∙t
product for a gaseous tox�cant �s expressed �n a volume fract�on of µl·l−1 (parts per m�ll�on; ppm) mult�pl�ed by m�nutes. D�v�s�on of th�s product by t
� y�elds the aver-
age effect�ve exposure concentrat�on (CAEE
) of the gas to wh�ch the an�mal was exposed, caus�ng �ncapac�tat�on (Equat�on 1).
(1)
FED �s a rat�o of the C∙t product for a gas to that product of the gas expected to produce a g�ven effect, such as t
�, on
an exposed subject, such as a rat, of average suscept�b�l�ty (65, 80, 139, 237, 263). When not used w�th reference to a spec�fic gas, the term FED represents the summa-t�on of FEDs for all gases �n a combust�on atmosphere. As a concept, FED may refer to any tox�colog�cal effect, �nclud�ng �ncapac�tat�on or lethal�ty. The FED of each gas �n a m�xture �s calculated by d�v�d�ng the C∙t value of the gas �n the m�xture by the correspond�ng C∙t value for exposure to the same gas alone for any effect such as t
� or t
d. For an add�t�ve effect of 2 gases �n the�r m�xture,
at t�me t, �nto exposure:
1,2,1 =+ tGastGas FEDFED (2)
FED �s a funct�on of t�me. The effect occurs when the FED reaches un�ty. Therefore, to be an add�t�ve effect, the rec�procal of the t
� value for the comb�ned gases should
be equal to the sum of the rec�procal t� values observed
w�th the �nd�v�dual gases, as
Such an FED-based model has been suggested to be appl�ed to the evaluat�on of the tox�c�ty of smoke �n computer model�ng of a�rcraft fire s�tuat�ons (263). To be used as a pred�ct�ve tool to est�mate human surv�vab�l�ty �n full-scale a�rcraft cab�n fire tests, th�s model �ncluded l�terature data for CO
2, low oxygen, CO, HCN, hydrogen
fluor�de, hydrogen chlor�de, hydrogen brom�de, n�trogen d�ox�de, sulphur d�ox�de, acrole�n, and heat exposures and was based on exposures to s�ngle and m�xed gases on humans, pr�mates, rats, and m�ce at d�fferent phys�cal act�v�ty levels. In th�s model, FEDs were obta�ned for
i
i
i
tt
tAEE t
tCt
CdtC
i
×== ∫=
=0
)()()(
111HCNiCOiHCNCOi ttt
+=+
(3)
10
�ncapac�tat�on and for lethal�ty, and the exposure t�me requ�red for e�ther FED to reach un�ty represented the exposure t�me ava�lable to escape from the spec�fied fire env�ronment or to surv�ve post-exposure. The effect of CO
2 �n �ncreas�ng the uptake of other gases was factored
�nto the concentrat�on term �n the FED equat�on for all gases, w�th the except�on of CO
2 and oxygen. In th�s
regard, h�gher resp�ratory m�nute volumes, because of CO
2 exposure, were found to be an �mportant factor
�n pred�ct�ng the t�me ava�lable to escape. Computer model�ng of human behav�or �n a�rcraft fire acc�dents, �nclud�ng tox�c�ty sub-model through the FED calcula-t�ons, has been elaborated (124).
3.4.3 Carboxyhemoglobin (COHb) and Blood Cyanide Ion (CN¯)
It �s well-establ�shed that carbon-conta�n�ng substances generate CO upon burn�ng, whereas n�trogen-conta�n-�ng substances also produce HCN (53, 64, 113, 123, 138, 244). These chem�cal spec�es are 2 pr�mary tox�c combust�on gases and are present �n relat�vely h�gh con-centrat�ons �n smoke. Both gases are present �n the blood of fire v�ct�ms (18, 68, 170, 183, 185, 253, 290). S�nce both gases have adverse effects on the central nervous system funct�ons (129, 158, 258), exclud�ng burn and phys�cal �njur�es, the pr�mary cause of �ncapac�tat�on or death �s attr�buted to exposures to these 2 gases. Other smoke const�tuents may also be tox�c, but they are gen-erally present at low concentrat�ons, thus are unable to produce a cons�derable degree of the acute undes�red effects. However, they may have the potent�al to produce delayed tox�c effects, depend�ng upon the durat�on and frequency of exposure to those products and the�r chem�cal structures. The hydrocarbon const�tuents of smoke have the capab�l�ty of adversely affect�ng the central nervous system funct�ons, as well.
S�nce a�rcraft mater�als do conta�n carbon and n�tro-gen, they generate CO and HCN upon burn�ng, and a�r passengers could be exposed to these gases by �nhal�ng smoke �n the unfortunate event of �n-fl�ght or post-crash fires. The actual degree of tox�c�ty produced by smoke can be establ�shed �n the v�ct�ms of fire by the analys�s of the�r blood for CO as COHb and HCN as CN¯. Var�ous analyt�cal methods for the blood analys�s of COHb and CN¯ are summar�zed �n Tables III and IV.
Although much research has been conducted �n es-tabl�sh�ng the relat�onsh�p between CO and/or HCN exposure doses and tox�colog�cal responses, there has been spars�ty �n exam�n�ng the relat�onsh�p between blood concentrat�ons of COHb and/or CN¯ and a tox�colog�cal response. In v�ew of the suggest�on that passenger protec-t�ve breath�ng equ�pment protect a�rcraft passengers from smoke for 5 m�n dur�ng an evacuat�on phase and for 35
m�n dur�ng an �n-fl�ght-plus-evacuat�on phase (114), t�
was determ�ned at 2 CO concentrat�ons that produce 5- and 35-m�n t
�s �n rats (245). Also, blood COHb
saturat�on was determ�ned �n rats exposed to these CO concentrat�ons at �ntervals less than t
�. At the end of each
exposure �nterval and at �ncapac�tat�on, rats were qu�ckly removed from the cage and k�lled for blood collect�on and COHb quant�tat�on. The observed reach�ng of COHb to a max�mal level before �ncapac�tat�on suggests that blood COHb saturat�on levels may not necessar�ly be �nd�cat�ve of the onset of �ncapac�tat�on. In s�m�lar exper�ments w�th HCN, t
� and blood CN¯ at t
� for 2 HCN concentrat�ons
that produce 5- and 35 m�n t�s were determ�ned �n rats
(60). Blood CN¯ levels as a funct�on of HCN exposure t�me were also measured. Blood CN¯ levels �ncreased as a funct�on of HCN exposure t�me, but the blood CN¯
level at the 5-m�n t� was half of the 35-m�n blood CN¯
level, and the HCN gas uptake rate at 184 ppm was about 3 t�mes that at 64 ppm. F�nd�ngs suggested that the blood CN¯ level at �ncapac�tat�on may vary substant�ally, depend�ng upon the HCN exposure concentrat�on. An equat�on was proposed for pred�ct�ng blood CN¯ levels �n rats (Equat�on 4).
(4)where
Ccn- �s blood CN¯ concentrat�on �n µg·ml−1;Chcn �s HCN exposure concentrat�on �n ppm;t �s exposure t�me �n m�n; andK �s a constant w�th the value of 2.2 × 10 –3.
3.4.4 COHb and Blood CN¯ Interactive EffectsExposures to CO-HCN m�xtures have demonstrated
that these gases have add�t�ve effects, that �s, shorter t�s
(Equat�on 3), but the result�ng concentrat�ons of COHb and blood CN¯ at �ncapac�tat�on are not well defined. These undefined relat�onsh�ps between COHb and blood CN¯ concentrat�ons and the onset of �ncapac�tat�on make the �nterpretat�on of postmortem levels d�fficult for med�-cal acc�dent �nvest�gators. Therefore, t
� was determ�ned �n
laboratory rats exposed to 2 CO-HCN m�xtures cons�st-�ng of CO and HCN concentrat�ons that produce 5- and 35-m�n t
�s �n �nd�v�dual gas exposures (65, 237). In the
h�gh concentrat�on CO-HCN m�xture, the resultant t� was
shortened from 5 m�n to 2.6 m�n; COHb dropped from 81% to 55% and CN¯ from 2.3 µg·ml−1 to 1.1 µg·ml−1. At the lower concentrat�on CO-HCN m�xture, where the resultant t
� reduced from 35 m�n to 11.1 m�n, COHb
dropped from 71% to 61%, and blood CN¯ decreased from 4.2 µg·ml–1 to 1.1 µg·ml–1.
Both the C∙t-based FED model and t� calculat�ons from
Equat�ons 2 and 3 �nd�cated that CO and HCN have add�t�ve effects on t
� at h�gh concentrat�ons and could
( ) ( ) KtCC HCN CN¯ =×÷
11
Tabl
e III
. Ana
lytic
al M
etho
ds fo
r Det
erm
inin
g C
OH
b C
once
ntra
tions
in B
lood
Met
hod
Prin
cipl
e, S
ensi
tivity
, and
Lim
itatio
n R
efer
ence
Who
le-b
lood
oxi
met
ry
Sim
ulta
neou
s aut
omat
ed d
iffer
entia
l vis
ible
spec
trom
etry
at v
ario
us c
hara
cter
istic
wav
elen
gths
.
CO
Hb
as lo
w a
s 10%
in fr
esh
bloo
d fr
om li
ve v
ictim
s (ac
cura
cy: 1
2%).
Suita
ble
for f
resh
hep
arin
ized
blo
od a
nd m
aybe
uns
uita
ble
for p
utrid
or c
lotte
d bl
ood.
Not
e: E
thyl
ened
iam
inet
etra
acet
ate
(ED
TA) c
ould
be
used
with
CO
-Oxi
met
er (7
4). C
itrat
e, fl
uorid
e,
oxal
ate,
and
ED
TA c
ause
err
ors w
ith A
VO
Xim
eter
(7).
Frei
reic
h et
al.
(121
); C
O-
Oxi
met
er (7
4);
AV
OX
imet
er (7
)
Palla
dium
chl
orid
e re
duct
ion
Rel
ease
of C
O fr
om C
OH
b by
sulfu
ric a
cid
adde
d to
blo
od in
the
oute
r rim
of a
Con
way
cel
l, re
duct
ion
of p
alla
dium
chl
orid
e in
the
cent
re w
ell o
f the
cel
l to
palla
dium
, and
mea
sure
men
t of a
bsor
banc
e at
278
nm
of t
he re
mai
ning
unr
eact
ed p
alla
dium
chl
orid
e so
lutio
n in
the
cent
re w
ell a
nd o
f a n
ew a
liquo
t of t
he
palla
dium
chl
orid
e so
lutio
n.
Una
ble
to m
easu
re C
OH
b be
low
10%
(coe
ffic
ient
of v
aria
tion:
± 5
.2%
), co
uld
be u
sed
for a
naly
zing
fr
esh
or u
ncoa
gula
ted
ante
mor
tem
or p
ostm
orte
m b
lood
.
Not
e: C
OH
b sa
tura
tion
can
be c
alcu
late
d by
det
erm
inin
g th
e co
ncen
tratio
n of
tota
l hem
oglo
bin
in b
lood
(7
, 74,
110
, 115
). Pr
esen
ce o
f a sh
iny
blac
k fil
m o
f pal
ladi
um o
n th
e pa
lladi
um c
hlor
ide
solu
tion
may
su
gges
t pre
senc
e of
CO
Hb
> 30
%. P
utrid
blo
od m
ay n
ot b
e su
itabl
e fo
r ana
lysi
s. Su
lfide
s pre
sent
in
putri
d bl
ood
in la
rge
conc
entra
tions
inte
rfer
e w
ith a
naly
sis,
but s
uch
inte
rfer
ence
can
be
rect
ified
by
usin
g a
satu
rate
d le
ad a
ceta
te-a
cetic
aci
d so
lutio
n in
pla
ce o
f sul
furic
aci
d as
the
CO
rele
asin
g re
agen
t.
Will
iam
s et a
l. (2
97);
Will
iam
s (29
5, 2
96)
Vis
ible
spec
troph
otom
etry
(c
alib
ratio
n cu
rve)
Hem
olys
is o
f red
blo
od c
ells
by
amm
oniu
m h
ydro
xide
, tre
atm
ent o
f the
hem
olys
ate
by so
dium
dith
ioni
te
to re
duce
met
hem
oglo
bin
(Met
Hb)
and
oxy
hem
oglo
bin
(Oxy
Hb)
to d
eoxy
hem
oglo
bin
(HH
b), a
nd
mea
sure
men
t of t
he a
bsor
banc
e at
540
nm
, a w
avel
engt
h of
max
imum
abs
orba
nce
for C
OH
b, a
nd a
t 57
9 nm
, a w
avel
engt
h at
whi
ch th
e sp
ectra
of v
ario
us sp
ecie
s of H
Hb
have
the
sam
e ab
sorb
ance
(is
obes
tic p
oint
).
Not
e: A
ratio
of a
bsor
banc
e va
lues
at 5
40 n
m a
nd 5
79 n
m is
use
d to
det
erm
ine
% C
OH
b in
the
spec
imen
fr
om a
cal
ibra
tion
curv
e.
Acc
urat
e es
timat
ion
of C
OH
b 1
0%, s
uita
ble
for f
resh
or u
n-co
agul
ated
ant
emor
tem
or p
ostm
orte
m
bloo
d, b
ut u
nsui
tabl
e fo
r put
rid b
lood
as r
esul
ting
pigm
ents
can
dis
tort
CO
Hb
and
HH
b sp
ectra
Win
ek a
nd P
rex
(298
); D
ougl
as (1
04);
Tiet
z an
d Fi
erec
k (2
72);
Bla
nke
(25)
;San
ders
on e
t al.
(246
); C
anfie
ld e
t al.
(43,
44)
Vis
ible
spec
troph
otom
etry
(C
O sa
tura
tion)
Satu
ratio
n of
Par
t 1 o
f the
3 p
arts
of b
lood
hem
olys
ate
with
CO
and
of
Part
2 w
ith o
xyge
n (n
o tre
atm
ent
of P
art 3
with
any
gas
), ad
ditio
n of
sodi
um d
ithio
nite
to a
ll th
e 3
parts
to re
duce
Met
Hb
and
Oxy
Hb
to
HH
b, a
nd d
eter
min
atio
ns o
f rat
ios o
f the
abs
orba
nce
valu
es o
f the
solu
tions
at 5
40 n
m a
nd 5
79 n
m to
fin
d ou
t % C
OH
b in
the
spec
imen
by
usin
g a
mat
hem
atic
al re
latio
nshi
p ca
pabl
e of
acc
urat
ely
mea
surin
g 1
0% C
OH
b in
fres
h an
d po
stm
orte
m b
lood
stor
ed w
ith so
dium
fluo
ride
and
pota
ssiu
m o
xala
te.
Not
e: C
lotte
d bl
ood
may
be
used
afte
r hom
ogen
izat
ion,
but
old
or p
utrid
blo
od m
ay in
terf
ere
with
an
alys
is.
Win
ek a
nd P
rex
(298
); Sa
nder
son
et a
l. (2
46);
Can
field
et a
l. (4
3, 4
4);
Rod
key
et a
l. (2
30);
Wid
dop
(293
); U
ges (
279)
12
Vis
ible
spec
troph
otom
etry
(w
ithou
t CO
sa
tura
tion)
Hem
olys
is o
f red
cel
ls o
f blo
od sp
ecim
ens,
redu
ctio
n of
Met
Hb
and
Oxy
Hb
to H
Hb,
and
cal
cula
tion
of
ratio
s of t
he a
bsor
banc
e va
lues
of t
he sp
ecim
ens a
t 540
nm
and
579
nm
.
Not
e: A
bsor
banc
e ra
tios a
re u
sed
to d
eter
min
e %
CO
Hb
in th
e sp
ecim
en b
y us
ing
a m
athe
mat
ical
eq
uatio
n in
rela
tion
to a
pos
itive
CO
Hb
cont
rol p
repa
red
in h
uman
blo
od b
y us
ing
CO
.
Cap
able
of a
ccur
atel
y m
easu
ring
10%
CO
Hb
in fr
esh
and
post
mor
tem
blo
od sa
mpl
es st
ored
with
so
dium
fluo
ride
and
pota
ssiu
m o
xala
te. (
Als
o, se
e pr
evio
us m
etho
d.)
Win
ek a
nd P
rex
(298
); Sa
nder
son
et a
l. (2
46);
Can
field
et a
l. (4
3, 4
4)
Hea
dspa
ce g
as
chro
mat
ogra
phy
(nic
kel-h
ydro
gen
redu
ctio
n)
Con
vers
ion
of M
etH
b an
d O
xyH
b to
HH
b by
sodi
um d
ithio
nite
in 2
sepa
rate
aliq
uots
of b
lood
sam
ples
; sa
tura
tion
of 1
aliq
uot w
ith C
O (n
o C
O tr
eatm
ent o
f the
seco
nd a
liquo
t); re
leas
e of
CO
from
bot
h bl
ood
aliq
uots
by
a fe
rric
yani
de o
r pho
spho
ric a
cid
solu
tion;
inje
ctio
n of
hea
dspa
ce a
ir sa
mpl
es o
f the
CO
-sa
tura
ted
and
non-
CO
trea
ted
sam
ple
aliq
uots
on
a ga
s chr
omat
ogra
ph e
quip
ped
with
a c
olum
n, a
m
etha
natio
n un
it (n
icke
l cat
alys
t and
hyd
roge
n un
it); f
lam
e io
niza
tion
dete
ctio
n of
met
hane
; and
ca
lcul
atio
n of
% C
OH
b le
vel i
n a
bloo
d sa
mpl
e by
com
parin
g m
etha
ne p
eaks
of t
he C
O-s
atur
ated
or
igin
al b
lood
sam
ple
and
of th
e no
n-C
O tr
eate
d bl
ood
sam
ple.
Cap
able
of a
ccur
atel
y de
term
inin
g C
OH
b at
the
leve
ls e
qual
to o
r gre
ater
than
10%
in fr
esh
bloo
d an
d po
stm
orte
m b
lood
sam
ples
.
Not
e: C
lotte
d bl
ood
can
be h
omog
eniz
ed p
rior t
o us
e.Pu
trid
bloo
d an
d bo
th h
epar
in a
nd so
dium
flu
orid
e-po
tass
ium
oxa
late
trea
ted
bloo
d ca
n be
use
d fo
r ana
lysi
s.
Grif
fin (1
30);C
arde
al e
t al.
(45)
Hea
dspa
ce g
as
chro
mat
ogra
phy
(ther
mal
con
duct
ivity
de
tect
ion)
Sepa
ratio
n of
the
subm
itted
sam
ple
into
2 p
arts
; tre
atm
ent o
f bot
h pa
rts w
ith so
dium
dith
ioni
te to
redu
ce
Met
Hb
and
Oxy
Hb
to H
Hb
satu
ratio
n of
1 p
art w
ith C
O (o
ther
use
d w
ithou
t CO
-trea
tmen
t); re
leas
e of
C
O fr
om th
e bo
th p
arts
by
sulfu
ric a
cid
with
sapo
nin;
inje
ctio
n of
hea
dspa
ce a
ir sa
mpl
es o
f the
CO
-sa
tura
ted
and
the
non-
CO
trea
ted
sam
ples
ont
o a
mic
ro-g
as c
hrom
atog
raph
; and
com
paris
on o
f gas
ch
rom
atog
raph
CO
pea
ks o
f orig
inal
blo
od sa
mpl
e (n
on-C
O tr
eate
d) a
nd o
f the
CO
-sat
urat
ed b
lood
sa
mpl
e, th
ereb
y ca
lcul
atio
n of
% C
OH
b le
vel i
n a
bloo
d sa
mpl
e.
Not
e: F
or se
nsiti
vity
and
lim
itatio
n, se
e pr
evio
us m
etho
ds.
Ende
cott
et a
l. (1
13);L
ewis
et
al.
(174
)
Tabl
e III
. (co
ntin
ued)
13
Tabl
e IV
. Ana
lytic
al M
etho
ds fo
r Det
erm
inin
g C
N¯
Con
cent
ratio
ns in
Blo
od
Met
hod
Prin
cipl
e, S
ensi
tivity
, and
Lim
itatio
na R
efer
ence
Col
orim
etry
(p
-nitr
oben
zald
ehyd
e an
d o-
dini
trobe
nzen
e)
Rea
ctio
n of
CN
¯ pr
esen
t in
bloo
d w
ith p
-nitr
oben
zald
ehyd
e an
d o-
dini
trobe
nzen
e un
der a
n al
kalin
e co
nditi
on a
nd p
rodu
ctio
n of
a v
iole
t col
or, s
ugge
stin
g th
e pr
esen
ce o
f a p
oten
tially
toxi
c C
N¯
conc
entra
tion,
a q
uick
qua
litat
ive
met
hod.
Det
ecta
ble
min
imum
CN
¯ co
ncen
tratio
n by
dire
ctly
usi
ng th
e sp
ecim
en: 0
.3 μ
g·m
l1 and
by
diff
usio
n: 0
.05
μg·m
l1
Rie
ders
(229
); G
uilb
ault
and
Kra
mer
(131
); D
unn
and
Siek
(105
)
Vis
ible
spec
troph
otom
etry
Li
bera
tion
of H
CN
from
blo
od b
y ac
idifi
catio
n an
d m
icro
diff
usio
n, tr
appi
ng o
f HC
N in
a d
ilute
al
kalin
e so
lutio
n, a
nd c
onve
rsio
n of
HC
N to
cya
noge
n ch
lorid
e af
ter r
eact
ing
with
chl
oram
ine-
T.
Subs
eque
nt re
actio
n be
twee
n cy
anog
en c
hlor
ide
and
pyrid
ine
to fo
rm N
-cya
nopy
ridin
ium
chl
orid
e,
follo
wed
by
a cl
eava
ge re
actio
n to
form
an
anil
of g
luta
coni
c al
dehy
des a
nd, t
hen,
cou
plin
g w
ith
barb
ituric
aci
d to
gen
erat
e a
red-
pink
ish,
hig
hly
reso
nant
pro
duct
, sug
gest
ing
pres
ence
of C
N¯.
Not
e: A
CN
¯ co
ncen
tratio
n of
as l
ow a
s 0.2
5 μg
·ml1
can
be e
asily
det
ecte
d by
pro
cess
ing
0.5
ml o
f bl
ood
spec
imen
. Blo
od o
r tis
sues
con
tain
ing
form
alin
can
not b
e an
alyz
ed, a
s for
mal
dehy
de re
acts
w
ith C
N¯
to fo
rm c
yano
hydr
in, w
hich
is q
uick
ly c
onve
rted
into
am
mon
ia a
nd g
lyco
lic a
cid.
Feld
stei
n an
d K
lend
shoj
(1
17);
Rie
ders
(228
); B
lank
e (2
4)
Hea
dspa
ce g
as
chro
mat
ogra
phy
(nitr
ogen
-ph
osph
orou
s det
ectio
n)
Equi
libra
tion
of b
lood
in th
e pr
esen
ce o
f ace
toni
trile
as a
n in
tern
al st
anda
rd in
a v
ial a
t roo
m
tem
pera
ture
for 3
0 m
in a
nd in
ject
ion
of th
e he
adsp
ace
of th
e vi
al o
nto
a ga
s chr
omat
ogra
ph
equi
pped
with
a n
itrog
en p
hosp
horu
s det
ecto
r to
dete
ct H
CN
and
ace
toni
trile
.
Line
arity
: 0.2
5–15
μg·
ml1 ; s
ensi
tivity
: 0.0
5 μg
·ml1
Zam
ecni
k an
d Ta
m (3
02);
McA
uley
and
Rei
ve (1
86)
Hea
dspa
ce g
as
chro
mat
ogra
phy
(ele
ctro
n ca
ptur
e de
tect
ion)
Libe
ratio
n of
HC
N fr
om b
lood
, chl
orin
atio
n of
HC
N to
cya
noge
n ch
lorid
e by
reac
tion
with
ch
lora
min
e-T,
and
inje
ctio
n of
hea
dspa
ce o
nto
a ga
s chr
omat
ogra
ph e
quip
ped
with
an
elec
tron
capt
ure
dete
ctor
.
Line
arity
: 0.
005–
1 μg
·ml1 ; s
uita
ble
for c
linic
al a
nd to
xico
logi
cal p
urpo
ses
Odo
ul e
t al.
(206
)
Spec
troph
otof
luor
imet
ry o
r hi
gh-p
erfo
rman
ce li
quid
ch
rom
atog
raph
y (f
luor
esce
nce
dete
ctio
n)
Tran
sfor
mat
ion
of C
N¯
by a
cidi
ficat
ion
from
blo
od to
HC
N, r
eact
ion
of C
N¯
in H
CN
with
2,3
-na
phth
alen
edia
ldeh
yde
and
taur
ine
in a
self
cont
aine
d sy
stem
, and
fluo
rimet
ric m
easu
rem
ent
(λex
cita
tion =
418
nm
; λem
issi
on =
460
nm
) of t
he re
actio
n pr
oduc
t, 1-
cyan
o-2-
benz
oiso
indo
le (1
-cy
ano[
f]ben
zois
oind
ole;
CB
I) d
eriv
ativ
e.
A sp
ecifi
c m
etho
d fo
r CN
¯ w
ith th
e de
tect
ion
limit
of 0
.002
μg·
ml1
CN
¯; li
near
ity: 0
.002
–1
μg·m
l1by
spec
troph
otom
etric
det
erm
inat
ion
and
0.00
2–5
μg·m
l1by
HPL
C d
eter
min
atio
n; su
itabl
e fo
r clin
ical
and
toxi
colo
gica
l pur
pose
s
Fels
cher
and
Wul
fmey
er
(118
)
14
Hig
h-pe
rfor
man
ce li
quid
ch
rom
atog
raph
y (m
ass
spec
trom
etric
det
ectio
n)
Usi
ng is
otop
ic p
otas
sium
cya
nide
(K13
C15
N) a
s an
inte
rnal
stan
dard
, mic
rodi
ffus
ion
of C
N¯
and
13C
14N
¯ fr
om b
lood
as H
CN
and
H13
C14
N, r
eact
ion
of C
N¯
and
13C
14N
¯ in
HC
N a
nd H
13C
14N
with
2,
3-na
phth
alen
edia
ldeh
yde
and
taur
ine
in a
self
cont
aine
d sy
stem
to p
rodu
ce n
on-is
otop
ic a
nd
isot
opic
ana
logs
of C
BI,
and
qual
itativ
e an
d qu
antit
ativ
e de
term
inat
ion
of b
oth
CB
I ana
logs
by
high
pe
rfor
man
ce li
quid
chr
omat
ogra
phy-
mas
s spe
ctro
met
ric d
etec
tion.
Not
e: T
he m
olec
ular
wei
ght o
f the
isot
opic
CB
I–13
C14
N d
eriv
ativ
e is
mor
e by
2 a
tom
ic m
ass u
nits
th
an th
at o
f non
-isot
opic
CB
I–C
N d
eriv
ativ
e. T
his m
etho
d sh
ould
be
suita
ble
for c
linic
al a
nd
toxi
colo
gica
l pur
pose
s.
A si
mpl
e, ra
pid,
and
ext
rem
ely
spec
ific
met
hod;
det
ectio
n lim
it: 0
.005
μg·
ml1 ; l
inea
rity:
0.0
15–3
μg
·ml1
Trac
qui e
t al.
(273
)
a Fres
h an
d po
stm
orte
m b
lood
sam
ples
cou
ld b
e an
alyz
ed b
y th
e m
ajor
ity o
f met
hods
incl
uded
her
ein.
Clo
tted
bloo
d m
ay a
lso
be a
naly
zed
afte
r hom
ogen
izat
ion.
Oth
er sa
mpl
e ty
pes t
hat c
an b
e an
alyz
ed a
re p
lasm
a, se
rum
, gas
tric
cont
ent,
cere
bros
pina
l flu
id, u
rine,
and
tiss
ue h
omog
enat
es. O
nly
33%
of t
he u
nmea
sura
ble
CN
¯ co
uld
be a
ttrib
uted
to th
e co
nver
sion
of C
N¯
to th
iocy
anat
e (S
CN
¯). S
odiu
m th
iosu
lfate
(Na 2
S 2O
3), t
he a
ntid
ote
for t
reat
ing
CN
¯ po
ison
ing,
has
bee
n re
porte
d to
inte
rfer
e w
ith c
olor
imet
ric, f
luor
imet
ric,
and
pote
ntio
met
ric m
etho
ds fo
r CN
¯ m
easu
rem
ent (
192,
267
, 288
).
Tabl
e IV
. (co
ntin
ued)
15
have other than add�t�ve effects at lower concentrat�ons. The lower t
�(CO + HCN) of 11.1 m�n �n compar�son to the
calculated value 16.4 m�n from Equat�on 3 and less than un�ty value �n Equat�on 2 could be assoc�ated w�th the l�m�tat�ons of the C∙t theory and �ts related FED concept (80, 156, 207). When the FED model was employed us-�ng % COHb and µg·ml–1 CN¯ levels at �ncapac�tat�on, the FEDs—that �s, FED
COHb + FED
HCN—were obta�ned
for the h�gh- and low-concentrat�on m�xtures of these 2 gases. The calculated values were correspond�ngly 1.16 and 1.12. In th�s regard, �t should be real�zed that the COHb level was almost l�near up to 5 m�n and started reach�ng a steady state before 11.1 m�n at the 35-m�n t
�
CO concentrat�on. Therefore, the FED model may have l�m�tat�ons for COHb and CN¯ levels, except �n the ex-tremely short exposure per�ods when both CO and HCN uptakes are l�near (65, 237). The evaluat�on of COHb and blood CN¯ values w�th the values from the s�ngle gas exposure stud�es �nd�cated that any alterat�on of the uptake of e�ther gas �n blood by the presence of the other gas was m�n�mal. These find�ngs suggested that changes �n COHb and blood CN¯ m�ght not be d�rectly correlated w�th the onset of �ncapac�tat�on and that postmortem blood levels should be carefully evaluated, part�cularly when both gases are present �n fire v�ct�ms.
Interpretat�on of elevated levels of COHb and CN¯ to the degree of tox�c�ty caused by CO and HCN becomes challeng�ng because both gases have �nteract�ve effects on the central nervous system (129, 138, 158, 258). When the FED concept (see Equat�on 2) �s appl�cable, the FED
CO + FED
HCN should equal un�ty for an add�t�ve
effect of CO and HCN. By employ�ng the FED model us�ng blood % COHb and µg·ml–1 CN¯ concentrat�ons �n place of CO and HCN effect�ve exposure doses, Equat�on 5 could be used to account for the add�t�ve effects caused by these gases (38, 39). In th�s equat�on, “Fract�onal Tox�c Concentrat�on” �n blood (FTC
Blood) �s
used �n place of FED.
It �s documented that CO at 70% COHb and HCN at 3.0 µg·ml–1 (µg/ml) CN¯ would alone cause lethal�ty (129, 137, 201). However, the FTC concept does not rule out other than add�t�ve effects of these gases. Therefore, the concentrat�ons of COHb and CN¯ �n blood and �nteract�ve potent�als of both spec�es should be carefully cons�dered when �nterpret�ng and correlat�ng the�r blood concentrat�ons w�th the tox�colog�cal effects. For example, the presence or absence of these spec�es �n blood would suggest whether the �nd�v�dual d�ed after �nhal�ng smoke or pr�or to the fire.
3.4.5 COHb and Blood CN¯ in Fire-Involved Aircraft Accident Fatalities
As ment�oned earl�er, occurrences of �n-fl�ght smoke and fire are rare �n modern a�rcraft. However, �f and when that happens, the consequences are deadly (2, 73, 187, 213, 275). For �nstance, the �nvolvement of an �n-fl�ght fire was deduced �n the Sw�ssa�r acc�dent that occurred on 2 September 1998, near Peggy’s Cove, Nova Scot�a, Canada (275). Compared to �n-fl�ght fires, post-crash (ground) fires are generally more common, pr�mar�ly or�g�nat�ng from sp�lled fuel around the a�rcraft. In the crash of Galaxy Fl�ght 203, on 21 January 1985, near Reno, Nevada, most v�ct�ms surv�ved the �mpact but succumbed to fire and tox�c gases (234). S�xty-e�ght persons d�ed at the scene, 2 d�ed dur�ng hosp�tal�zat�on, and 1 surv�ved. F�fty-four people d�ed �n the Br�t�sh A�r Tours Boe�ng 737 acc�dent at Manchester, Un�ted K�ngdom, on 22 August 1985 (185). F�re was �nvolved �n the acc�dent. Blood COHb and CN¯ were elevated �n most of the v�ct�ms. Volat�le substances were also detected �n the blood of the v�ct�ms and carbon part�cles �n the trachea and bronch�.
In such post-crash fires, a�rcraft occupants are frequent-ly unable to escape from the fire env�ronment because of phys�cal �njur�es and/or performance �mpa�rment from smoke-�nduced tox�c�ty and v�sual obscurat�on. Such �nab�l�ty leads to �ncapac�tat�on and death. Therefore, �t �s common to determ�ne COHb and blood CN¯ con-centrat�ons �n fire-assoc�ated a�rcraft acc�dent fatal�t�es to establ�sh the degree of tox�c�ty (67, 68, 185, 204).
3.4.6 Analytical Results Interpretation3.4.6.1 Analysis
Commonly used analyt�cal procedures for measur�ng COHb and CN¯ �n blood are summar�zed �n Tables III and IV. The blood qual�ty could affect the accuracy of the concentrat�ons of these spec�es; therefore, �t �s an analyt�cal and tox�colog�cal concern. From av�at�on acc�dent fatal�t�es, qual�ty blood samples are frequently d�fficult to obta�n. The qual�ty of the blood �s dependent upon the postmortem �nterval—that �s, the t�me between death and blood collect�on. Old or putr�d blood samples may �nterfere w�th the analys�s. Clotted blood samples could be homogen�zed pr�or to analys�s. Sol�d burned blood samples may not be su�table for analys�s, though the�r aqueous homogenates could be analyzed. However, �t would be d�fficult to �nterpret such analyt�cal values. The blood collect�on techn�que and conta�ner, the types of ant�coagulants and/or preservat�ves used, the sample storage cond�t�ons, the analys�s t�me after sample col-lect�on, the rat�o of surface area to volume of blood
(5)1µg/mL)(3.0¯(µg/mL)¯
%70%
¯ =+=+=CNCN
COHbCOHb
FTCFTCFTC SampleSampleCNCOHbBlood
16
exposed to the atmosphere, the storage cond�t�on and temperature, and the �n�t�al % COHb saturat�on (50) and blood CN¯ concentrat�on also adversely affect the outcome of such analyses.
3.4.6.2 COHb ConcentrationsAlthough COHb below 5% �s cons�dered normal,
healthy �nd�v�duals may accumulate up to 10% COHb by �nhal�ng CO-contam�nated a�r (17, 296). COHb concentrat�ons as h�gh as 17% have been documented �n heavy smokers (286). An approx�mately 20% decrease �n COHb levels as a funct�on of t�me has been reported �n postmortem blood samples collected from fire v�ct�ms (170). Therefore, COHb analyt�cal values may not reflect the true levels of th�s spec�es at the t�me of death, but they may represent approx�mate values at death. For a g�ven % COHb concentrat�on, effects may be more se-vere �n phys�cally act�ve subjects or follow�ng prolonged exposures of several hours (190, 214, 215). Because of a cons�derable range of sens�t�v�ty to CO po�son�ng �n the populat�on, fatal�t�es from CO exposures show a w�de range of COHb concentrat�ons, from approx�mately < 30% to 95% COHb (200). Tox�c�ty of CO po�son�ng �s assoc�ated w�th the central nervous and card�ovascular systems where�n the oxygen demand �s h�gh (129, 158, 258); COHb concentrat�ons and assoc�ated s�gns and symptoms are g�ven �n Table V (129).
3.4.6.3 CN¯ ConcentrationsBlood CN¯ concentrat�ons are also strongly affected
by the postmortem �nterval, decreas�ng by approx�mately 50% per day �n a cadaver (10, 90). CN¯ �n blood can be �n the HCN form. In �ts protonated form, CN¯ as HCN could be eas�ly d�ffused through the body and released �nto the surround�ng atmosphere, thereby reduc�ng CN¯ levels. Release of HCN from cyanomethaemoglob�n (cyano-MetHb) has been reported by heat denaturat�on, as well (252). The major�ty of the analyt�cal meth-ods measure total CN¯ or�g�nat�ng from both cr�t�cal (cyan�de-cytochrome ox�dase complex) and non-cr�t�cal (cyano-MetHb; erythrocytes) s�tes (65, 129, 158, 188, 284). Normal human blood concentrat�ons range from 0.0 to 0.30 µg·ml–1 �n nonsmokers and from 0.02 to 0.50 µg·ml–1 �n smokers (12, 184, 268). Or�g�nat�ng from cyanogen�c glycos�des or pyocyaneous organ�sms, CN¯ concentrat�ons up to 0.15 µg·ml–1 �n blood could be found �n adults w�thout symptoms (16, 21, 24, 29, 91, 92, 129). A CN¯ value of < 0.25 µg·ml–1 may not have tox�colog�cal relevance, as cl�n�cal man�festat�ons are observed at CN¯ concentrat�ons of ≥ 0.5 µg·ml–1 (Table VI) (129), though tox�c effects of CN¯ on fire v�ct�ms should not be solely based upon �ts blood concentrat�on (193, 194).
CN¯, a rap�dly act�ng tox�c chem�cal ent�ty, �s capable of caus�ng �ncapac�tat�on qu�ckly (129, 158, 258). As the CN¯ concentrat�on �ncreases, unava�lab�l�ty of oxygen to the central nervous system may cause hypox�c convuls�ons, followed by death due to resp�ratory arrest. Inhalat�on of HCN r�ch smoke �nduces hypervent�lat�on, thus �n-creas�ng the rate of uptake unt�l the v�ct�m collapses and becomes comatose. When the rate of uptake decreases, the v�ct�m may temporar�ly recover. Such recovery, however, may be short l�ved, lead�ng �nto a gradual but fatal decl�ne (214, 216). Although h�gh blood CN¯ concentrat�ons probably result from the release of sequestered CN¯ �n the red blood cells (8, 11, 14, 15, 274, 284) and blood concentrat�ons of CN¯ could be correlated w�th �ts tox�c�ty (13, 129, 188), the assoc�ated s�gns and symptoms may be more closely related to plasma CN¯ concentrat�ons than whole blood CN¯, as an unconsc�ous v�ct�m may recover qu�ckly of the cessat�on of exposure w�thout any decl�ne �n whole blood CN¯ (214, 216).
3.4.6.4 MetHb, Cyano-MetHb, and Sulfmethemoglobin (Sulf-MetHb)
Includ�ng CO and HCN, numerous spec�es could be produced dur�ng combust�on of substances (107, 113, 123, 136, 138, 244), and some of these may be very react�ve, thus may convert HHb to MetHb. MetHb may also be produced by heat (116) and by postmortem ox�dat�on of HHb (157, 203, 247). Smoke r�ch �n HCN, hydrogen sulfide, or sulfur-conta�n�ng substances may react w�th MetHb to form cyano-MetHb and sulf-MetHb (129). The latter could also be formed postmortem as hydrogen sulfide and sulfur spec�es are produced dur�ng putrefact�on.
Sulf-MetHb �nterferes w�th spectrophotometr�c ana-lyt�cal methods (74, 258), part�cularly when th�s spec�es �s present �n h�gh concentrat�ons. Spectral absorbance of sulf-MetHb �s s�m�lar to that of MetHb. Also, some analyt�cal methods do not account for cyano- and sulf-MetHb �n measur�ng total hemoglob�n. Therefore, % COHb results could be erroneously h�gh by us�ng those methods.
Dur�ng COHb measurements, sod�um d�th�on�te �s used as a reduc�ng agent to convert OxyHb and MetHb to HHb to max�m�ze the CO b�nd�ng capac�ty of the blood sample. However, �t has not been clearly establ�shed whether such d�th�on�te treatment would also reduce cyano- and sulf-MetHb to HHb, though polysulfides, th�osufate, and sulfate have been known to reduce sulf-MetHb to HHb (129). If these HHb-analogs, as well as OxyHb and MetHb, could not be completely converted to HHb by the d�th�on�te treatment, then the b�nd�ng capac�ty of the blood sample would not be max�mum,
17
Table V. Percent COHb and Associated Sign and Symptoms (129)
% COHb Signs and Symptoms
0–10 No symptoms
10–20 Tightness across forehead, possible slight headache, and dilation of cutaneous blood vessels
20–30 Headache and throbbing in temples, easily fatigued, and possibly dizziness
30–40 Severe headache, weakness, dizziness, confusion, vision dimness, nausea, vomiting, and collapse
40–50 Signs and symptoms same as above, but severity is higher; increased pulse and respiratory rate
50–60 Increased respiratory and pulse rate, coma, intermittent convulsions, and Cheyne-Stokes respiration
60–70 Coma, intermittent convulsions, depressed heart action and respiratory rate, and possible death
70–80 Weak pulse, slow respiration, respiratory failure, and death within a few hours
80–90 Death in less than an hour
> 90 Death in a few minutes
Table VI. Blood CN¯ Concentrations and Associated Toxicity (129)
Degree of Toxicity (Blood CN¯) Signs and Symptoms
Mild (0.5–1.0 μg·ml 1) Flushed, rapid pulse, conscious, and headache
Moderate (1.0–2.5 μg·ml 1) Stuporous but responsive to stimuli, tachycardia, and tachypnea
Severe ( 2.5 μg·ml 1) Comatose, unresponsive, hypotension, slow respirations, gasping, mydriasis, cyanosis at high concentration, and death
18
and thereby the observed % COHb values would be erroneously h�gher �n compar�son to the s�tuat�on when these hemoglob�n spec�es would have been completely reduced to HHb. Therefore, cyano-MetHb and sulf-MetHb at h�gh concentrat�ons may potent�ally �nterfere w�th the COHb analyses, thus may prov�de �naccurate analyt�cal results.
4 POSTMORTEM AVIATION FORENSIC TOXICOLOGY
4.1 Introductory CommentsThe field of Postmortem Aviation Forensic Toxicology falls
between the categor�es of Postmortem Forensic Toxicology and Human-Performance Forensic Toxicology. Per the�r defin�t�ons �n the forens�c tox�cology laboratory gu�de-l�nes (260), the former deals w�th the cause and manner of death, whereas the latter w�th human performance or behav�or. The fly�ng process �nvolves the �nteract�on between man and the mach�ne, and �t �s not only the equ�pment fa�lure, but also the performance �mpa�r-ment and/or abnormal behav�or of av�ators that m�ght contr�bute to an acc�dent. Such acc�dent could be fatal. The performance/behav�or-related changes �n av�ators may be because of the presence of fore�gn substances �n the�r system and/or of health reasons. Therefore, dur�ng av�at�on tox�cology evaluat�on, postmortem b�olog�cal samples from av�ators are analyzed for the presence of fore�gn substances—combust�on gases, ethanol/volat�les, and drugs—to establ�sh whether the fore�gn substance(s)-�nduced performance �mpa�rment/behav�oral abnormal�ty was the cause or a factor �n a part�cular av�at�on acc�dent (35, 41, 69, 262). Most of the drugs present �n the p�lot samples are �n the subtherapeut�c-to-therapeut�c concentrat�on range (6, 35, 41, 69, 250, 262), wh�ch �s cons�stent w�th the nature of postmortem av�at�on tox�-cology and could bas�cally be referred to as the human-performance assoc�ated postmortem forens�c tox�cology (260). The presence of drugs would also be suggest�ve of the�r underly�ng med�cal cond�t�ons for wh�ch they were treated.
Dur�ng fatal a�rcraft acc�dent �nvest�gat�ons, post-mortem samples are collected from p�lot fatal�t�es and tox�colog�cally evaluated �n a forens�c tox�cology fac�l-�ty. The fac�l�ty could be assoc�ated w�th a local or state agency �n some countr�es, wh�le w�th a federal agency �n others. In the Un�ted States, the tox�cology fac�l�ty �s located at CAMI (1, 69, 103). The sample subm�ss�on �s coord�nated through the FAA’s Office of Acc�dent Invest�gat�on by the Nat�onal Transportat�on Safety Board. Th�s Board �s respons�ble for �nvest�gat�ng all U.S. c�v�l�an a�rcraft acc�dents. In the major�ty of s�tuat�ons, the samples are from p�lots and cop�lots. Samples from
passengers and other crewmembers are also somet�mes subm�tted, depend�ng upon the nature of an acc�dent—for example, an acc�dent �nvolv�ng fire. Mult�ple types of postmortem spec�mens—blood, ur�ne, v�treous flu�d, sp�nal flu�d, bra�n, lung, heart, l�ver, k�dney, and/or other sample types—�n suffic�ent amounts are needed for analys�s (69), but th�s requ�rement frequently cannot be ach�eved �n those acc�dents �n wh�ch bod�es are scat-tered, d�s�ntegrated, comm�ngled, contam�nated, and/or putrefied. Glucose concentrat�ons �n v�treous flu�d and ur�ne samples are determ�ned, and �n those s�tuat�ons where�n glucose levels are elevated, blood hemoglob�n A
1c (HbA
1c; glycosylated hemoglob�n) �s also measured
to mon�tor d�abet�c p�lots, ensur�ng that the d�sease was �n control at the t�me of acc�dent, and to d�scover other p�lots w�th und�agnosed or unreported d�abetes (55). The postmortem forens�c samples are subm�tted to CAMI �n TOX-BOX ev�dence conta�ners. The contents of a TOX-BOX k�t and types, amounts, and analyt�cal su�tab�l�ty of postmortem spec�mens are deta�led �n a prev�ously publ�shed art�cle (69).
4.2 Analytical ComponentsEv�dence conta�ners w�th samples should be rece�ved
�n a secured, spec�fic area of the tox�cology fac�l�ty, and the samples should be access�oned follow�ng the standard operat�ng procedure of the laboratory. Depend�ng upon the types and amounts of subm�tted samples and the m�s-s�on of the laboratory, the follow�ng analyt�cal tox�cology tests should be performed (69):1) Blood CO as COHb by a spectrophotometr�c
method and confirmat�on by gas chromatography2) Blood CN¯ by a color�metr�c method and confirma-
t�on by another method, such by h�gh-performance l�qu�d chromatography
3) Ethanol/volat�les �n v�treous flu�d, ur�ne, blood, bra�n, muscle, and/or other t�ssues by dual cap�llary column-flame �on�zat�on detect�on by headspace gas chromatography
Note: The presence of ethanol �n l�qu�d sam-ples—v�treous flu�d, ur�ne, and blood—should be confirmed by a second method such as rad�at�ve energy attenuat�on. In those cases where�n etha-nol �s pos�t�ve �n ur�ne, ur�nary concentrat�ons of seroton�n metabol�tes—5-hydroxytryptophol (5-HTOL) and 5-hydroxy�ndole-3-acet�c ac�d (5-HIAA)—should be measured by l�qu�d chromatog-raphy-mass spectrometry and the�r rat�o should be calculated to conclude whether ethanol found �n the samples �s from sources other than �ngest�on. A concentrat�on rat�o value of < 15 pmol/nmol �s not cons�stent w�th ethanol �ngest�on; a value ≥ 15 pmol/nmol �s suggest�ve of ethanol �ngest�on (153, 154).
19
4) Blood and other t�ssue samples should be screened for: a) Controlled substances—amphetam�ne, barb�tu-
rates, benzod�azep�nes, cannab�no�ds, coca�ne, methamphetam�ne, op�ates, and phencycl�-d�ne—by rad�o�mmunoassay
b) Prescr�pt�on and nonprescr�pt�on drugs by h�gh-performance l�qu�d chromatography and gas chromatography-mass spectrometry
c) Add�t�onal drugs �n blood—acetam�nophen, phenyto�n, qu�n�d�ne, sal�cylate, and theophyl-l�ne—by fluorescence polar�zat�on �mmunoas-say.
5) Ur�ne should be screened for:a) Controlled substances—amphetam�ne, barb�tu-
rates, benzod�azep�nes, cannab�no�ds, coca�ne, methamphetam�ne, op�ates, and phencycl�d�ne—by fluorescence polar�zat�on �mmunoassay
b) Prescr�pt�on and nonprescr�pt�on drugs by h�gh-performance l�qu�d chromatography and gas chromatography-mass spectrometry
c) Add�t�onal drugs—acetam�nophen, phenyt-o�n, propoxyphene, qu�n�d�ne, sal�cylate, and theophyll�ne—by fluorescence polar�zat�on �mmunoassay.
6) Confirmatory/quant�tat�ve analys�s should be per-formed �n the samples where�n drug(s) was found dur�ng �n�t�al analyses (screen�ng). In other words, confirmatory/quant�tat�ve analyses should be per-formed �n the al�quots of the sample type, wh�ch was determ�ned as presumpt�vely pos�t�ve for drug(s) dur�ng the �n�t�al analys�s (screen�ng), and of at least 1 add�t�onal sample type (�f ava�lable) of the case. Preferred sample types are blood and ur�ne, but other sample types could also be used. Depend�ng upon the type of analyte, gas chromatography-mass spec-trometry, l�qu�d chromatography-mass spectrometry, or any other spec�fic techn�ques could also be used for confirmatory/quant�tat�ve analyses.
7) Glucose �n v�treous flu�d and ur�ne could be measured enzymat�cally and HbA
1c �n blood by latex �mmuno-
agglut�nat�on �nh�b�t�on methodology. Presence of glucose �n v�treous and ur�ne could be reconfirmed by color-sens�t�ve reagent str�ps.
8) Somet�mes, DNA profil�ng should also be performed on the samples of a case to ensure that the subm�t-ted samples or�g�nated from the same source. Th�s approach becomes necessary when there �s a reason to bel�eve that the samples m�ght have been com-m�ngled or m�smatched w�th the samples of other v�ct�ms dur�ng the sample collect�on (70).
9) Throughout the ent�re process of tox�colog�cal evaluat�on—that �s, from rece�v�ng the samples to d�spatch�ng the analyt�cal reports—a h�gh level of qual�ty assurance/qual�ty control should be ma�n-ta�ned (4, 260); th�s aspect could be eas�ly exempl�-fied by the prev�ously descr�bed FAA’s Postmortem Forens�c Tox�cology Profic�ency-Test�ng Program (4, 54, 260).
10) The cha�n-of-custody of postmortem forens�c samples and all records, �nclud�ng analyt�cal data, should be securely ma�nta�ned throughout the ent�re forens�c evaluat�on process.
S�nce the presence of drugs �n a p�lot’s system also suggests poss�ble assoc�ated med�cal cond�t�ons for wh�ch they m�ght have been taken, �dent�ficat�on and quant�ficat�on of parent drugs and the�r metabol�tes �n mult�-spec�mens are of relevance �n the field of forens�c sc�ence (56). Demonstrat�ng the presence of drug metabo-l�tes such as ∆9-tetrahydrocannab�nol (THC) carboxyl�c ac�d of THC and benzoylecgon�ne of coca�ne prov�des compell�ng ev�dence for use/abuse to the parent drug and fac�l�tates �nterpretat�on of results and �nvest�gat�on of a case, part�cularly when the metabol�tes are pharmacolog�-cally act�ve. Such analyses m�ght not be as helpful �f the metabol�tes are also marketed or ava�lable as drugs.
4.3 COHb and Blood CN¯ ConcentrationsAlthough �n-fl�ght fires �n modern a�rcraft are rare,
post-crash fires do occur (53, 64, 68, 177). F�re-�nvolved c�v�l passenger a�rcraft acc�dents cla�m�ng cons�derable number of fatal�t�es have been documented (32, 126). In av�at�on acc�dents, COHb and blood CN¯ analyses are performed to establ�sh poss�ble exposure of v�ct�ms to smoke from �n-fl�ght/post-crash fires or to CO from faulty exhaust/heat�ng systems. The elevated COHb, as well as CN¯, �n blood would suggest that the v�ct�m was al�ve and �nhaled smoke. If only COHb �s elevated, the acc�dent (or death) could be attr�buted to the contam�na-t�on of the a�rcraft �nter�or by CO.
The tox�colog�cal assessment of 485 fatal a�rcraft ac-c�dents that occurred �n the Un�ted K�ngdom between 1955 and 1979 found COHb concentrat�ons ≥ 10% �n 90 fatal�t�es of the 439 evaluated (143). In another study for the 1967–1972 per�od, tox�cology revealed elevated COHb of d�rect �mportance �n 19% of the 113 acc�dents (23). Blood analys�s of p�lot fatal�t�es of general av�at�on acc�dents (October 1968–September 1974) revealed COHb �n excess of 10% �n 79 of the 1,345 cases and elevated CN¯ �n 16 of the 1,345 cases (165). Elevated COHb was reported �n 13 of the 2,449 p�lots k�lled �n general av�at�on operat�ons (1973–1977) and was due to faulty heaters or exhaust systems (166). Three cases w�th
20
COHb > 10% have been reported �n 202 general av�a-t�on acc�dents �n a 1970 study (255). In an FAA study, analys�s of samples from 377 av�at�on fatal�t�es dur�ng October 1988–September 1989 concluded COHb at < 10% �n 94% of the cases and cyan�de at < 0.5 µg·ml−1 �n 96% of the cases (161). Tox�colog�cal find�ngs �n m�l�tary a�rcraft fatal�t�es �nvest�gated by the D�v�s�on of Forens�c Tox�cology at the U.S. Armed Forces Inst�tute of Pathol-ogy from 1986 to 1990 suggested COHb concentrat�ons > 10% �n 4.3% of the 535 cases (159).
Accord�ng to a 2001 study by Chaturved� et al. (68), 1,571 (41%) fatal�t�es (1,012 av�at�on acc�dents) out of the 3,857 fatal�t�es (2,837 av�at�on acc�dents) occurr�ng dur�ng 1991–1998 were fire-assoc�ated. There were 1,820 non fire-related acc�dents, and the fire status of 5 acc�dents was unknown. There were fewer fire-related fatal�t�es and assoc�ated acc�dents �n the category where�n COHb ≥ 10% and CN¯ ≥ 0.25 µg·ml−1 than that �n the category of where�n COHb < 10% and CN¯ < 0.25 µg·ml−1. No �n-fl�ght fire was documented �n the former category; however, �n-fl�ght fires were reported �n 14 acc�dents (18 fatal�t�es) �n the latter category. There were 15 non-fire acc�dents �nvolv�ng 17 fatal�t�es. In these fatal�t�es, only COHb (10–69%) was elevated. Th�s study suggested that av�at�on fire acc�dents were fewer than non-fire acc�dents and confirms that av�at�on acc�dents related to �n-fl�ght fires and CO-contam�nated �nter�ors are rare occurrences. (Readers may also refer to the Aviation Combustion Toxi-cology sect�on for add�t�onal deta�ls.)
4.4 EthanolDepend�ng upon the nature of a fatal av�at�on acc�dent,
the bod�es of v�ct�ms are frequently scattered, d�s�nte-grated, and/or putrefied. It �s well-establ�shed that the body �s �nvaded by m�crobes after death, and these l�v�ng m�cro-organ�sms are �nvolved �n putrefact�on processes, lead�ng to the postmortem product�on of ethanol �n the body (22, 75, 160, 163). The extent of putrefact�on �s l�nked to the cond�t�on of the body, wh�ch �s affected by the sever�ty of �njur�es, the t�me between the death and the d�scovery of the body (postmortem �nterval), and the env�ronmental factors. Indeed, the postmortem produc-t�on of ethanol �n av�at�on acc�dents has been an �ssue �nvest�gated for many years (89), but the product�on of ethanol after the postmortem collect�on of flu�d samples can be m�n�m�zed by collect�ng them �n conta�ners con-ta�n�ng sod�um fluor�de and stor�ng the collected samples �n cold (69, 89, 172). Ethanol product�on by Candida albicans �n postmortem human blood samples has been reported, and the necess�ty of �mmed�ately add�ng sod�um fluor�de to samples for ethanol analys�s to prevent further ethanol product�on, �f any, has been reemphas�zed (301). A polymerase cha�n react�on (PCR)-based method for
detect�ng the presence of common ethanol produc�ng m�crob�al contam�nants—Escherichia coli, Proteus vul-garis, and Candida albicans—�n human blood has been publ�shed by us�ng a set of DNA pr�mers des�gned for use �n PCR to ampl�fy and detect the genom�c DNA from humans and the 3 test m�croorgan�sms (163). Th�s method �s su�table for rap�dly �dent�fy�ng m�crob�al con-tam�nants �n postmortem blood, as well as sol�d t�ssue, samples (163, 287).
Because of the �mpact generally encountered dur�ng a�rcraft crashes, extens�ve abdom�nal damage and open wounds frequently occur �n the fatal�t�es. Such damage and wounds, thus, �ncrease the potent�al for m�crob�al �nvas�on and for putrefact�on; �nterpretat�on of ethanol concentrat�ons �n autops�ed spec�mens from v�ct�ms �s h�ghly arguable, and great caut�on �s needed to reach val�d conclus�ons of whether the deceased had consumed ethanol before death (160). In the past, the postmortem ethanol product�on was �nferred from the presence of acetaldehyde, acetone, 2-butanol, and other volat�les, but th�s bas�s may not have always been correct (42). For example, �n a study �nvolv�ng av�at�on acc�dent fatal�t�es, several cases w�th postmortem ethanol had no other vola-t�les, and volat�le compounds were found �n several cases where no ethanol was present (42). In add�t�on, a case was found �n wh�ch the relat�ve ethanol concentrat�ons �n blood, b�le, and v�treous humor were cons�stent w�th the �ngest�on of ethanol, but acetaldehyde, acetone, and 2-butanol were also found �n blood. These observat�ons �nd�cate that the presence or absence of other volat�les does not necessar�ly establ�sh postmortem ethanol product�on (42). Determ�nat�on of ethanol concentrat�ons �n var�ous sample types—v�treous humor, ur�ne, bra�n, l�ver, k�dney, and muscle—�s helpful �n establ�sh�ng the d�str�but�on of ethanol. Based upon the d�str�but�on find�ngs, �t could be sc�ent�fically deduced whether ethanol was consumed before death or produced postmortem. The presence of ethanol �n blood and �ts absence �n v�treous flu�d or bra�n would be �nd�cat�ve of postmortem format�on of ethanol. Interpretat�on of postmortem product�on of ethanol and other assoc�ated factors has been covered �n a cr�t�cal rev�ew by O’Neal and Pokl�s (205).
Of the 485 U.K. fatal a�rcraft acc�dents (1955–1979), 28 were found to have med�cal cause (143). Seven of these 28 crashes were due to alcohol consumpt�on. Dur-�ng 1967–1972 �n the UK, a�rcraft acc�dent tox�cology revealed that the presence of ethanol was of �mportance �n 7% of the 113 acc�dents (23). In the U.S., blood ethanol concentrat�ons were found �n excess of 0.05% �n 117 of the 1,345 general av�at�on acc�dent p�lot fatal�t�es (October 1968–September 1974) (165), �n 226 of the 2,623 p�lots k�lled dur�ng agr�cultural and general av�a-t�on operat�ons (1973–1977) (166), and �n 28 of the 202
21
p�lots �nvolved �n fatal general av�at�on acc�dents (255). In an FAA study, the presence of ethanol at > 10 mg·dl−1 was found �n 14.8% of the 377 av�at�on fatal�t�es dur�ng October 1988 to September 1989, but only 4.5% were determ�ned to be due to ethanol �ngest�on (161). Pos�-t�ve ethanol find�ngs �n m�l�tary a�rcraft fatal�t�es from 1986–1990 were suggest�ve of postmortem format�on than antemortem consumpt�on (159).
In a study by Canfield et al. (42), 79 (8%) of 975 v�ct�ms of fatal a�rcraft acc�dents (1989–1990) had blood ethanol ≥ 0.04% (40 mg·dl−1), a legal blood alcohol con-centrat�on under the FAA regulat�on at wh�ch no person may operate or attempt to operate an a�rcraft (48, 233). Based on the d�str�but�on of ethanol �n ur�ne, v�treous humor, blood, and t�ssue (42), �t was determ�ned that 21 of the pos�t�ve cases (27%) were from postmortem ethanol product�on. Postmortem ethanol product�on was > 0.15% (150 mg·dl−1) �n 2 cases. Add�t�onally, 22 (28%) of the pos�t�ve cases were found to be from the �ngest�on of ethanol. The or�g�n of the ethanol could not be establ�shed �n 36 cases (45%). A study �nvolv�ng the postmortem tox�cology analys�s (1989–1993) of 1,845 av�at�on acc�dent p�lot fatal�t�es revealed the presence of ethanol at or above the legal l�m�t of 0.04% �n 146 p�lots (35, 48, 233). S�m�larly, ethanol at or above the legal l�m�t was found �n 124 out of 1,683 p�lots dur�ng 1994–1998 (41) and �n 101 out of 1,587 p�lots dur�ng 1999–2003 (58, 59). The presence of ethanol w�th selec-t�ve seroton�n reuptake �nh�b�tors (SSRIs) (6) and w�th first-generat�on H
1 ant�h�stam�nes (250) has also been
reported �n av�at�on acc�dent p�lot fatal�t�es. The research on the product�on of ethanol has now
been focused on develop�ng var�ous b�ochem�cal tests or markers of postmortem synthes�s of ethanol (160). These tests/markers �nclude the ur�nary metabol�tes of seroton�n and non-ox�dat�ve metabol�tes of ethanol such as ethyl glucuron�de (34, 133, 153, 154, 160, 195). Add�t�onally, ethyl sulfate and the rat�o between 5-hydroxytryptophol-glucuron�de and 5-HIAA have further been emphas�zed as b�omarkers for recent alcohol �ngest�on w�th longer detect�on t�mes than measurement of ethanol �tself (148). However, there has been debate about the total rel�ab�l�ty of the b�omarkers (140). The format�on of ethyl glucuro-n�de and ethyl sulfate has been reported even follow�ng �nhalat�on of ethanol vapors (155). D�sappearance of ethyl glucuron�de dur�ng heavy putrefact�on has also been �mpl�ed (149). On the other hand, rat�os of concentra-t�ons of seroton�n metabol�tes, 5-HTOL and 5-HIAA, �n ur�ne have effect�vely been used for conclud�ng whether ethanol found �n the samples �s from sources other than �ngest�on (34, 133, 153, 154). The use of the ur�nary 5-HTOL:5-HIAA concentrat�on rat�o as a marker of recent ethanol consumpt�on stems from the fact that the
ox�dat�ve deam�nat�on of seroton�n to 5-HIAA �s altered after ethanol consumpt�on (89). Such alterat�on causes an �ncrease �n the concentrat�on of 5-HTOL, wh�ch �s normally < 1% of 5-HIAA. Recent consumpt�on of ethanol �ncreases th�s proport�on of seroton�n metabol�tes. Accord�ngly, a concentrat�on rat�o (5-HTOL:5-HIAA) value of < 15 pmol/nmol �s not cons�stent w�th ethanol �ngest�on, wh�le a value ≥ 15 pmol/nmol �s suggest�ve of ethanol �ngest�on (34, 153, 154).
4.5 Drugs4.5.1 Commonly Used and Abused Drugs
Although the top�c of tak�ng med�cat�ons by av�ators has been touched upon by H�ll (143) �n the 1986 study cov-er�ng 485 U.K. fatal a�rcraft acc�dents (1955–1979), the U.K. a�rcraft acc�dent tox�cology exper�ence (1967–1972) �s elaborated �n a study by Blackmore (23). Th�s study �nvolved 113 a�rcraft, encompass�ng 184 crew and 207 passengers. Cyclopenetam�ne, methaqualone, sal�cylate, and val�um were detected �n 4 p�lots of the fatal acc�-dents. In the U.S., a tox�colog�cal study w�th 202 p�lot fatal�t�es d�sclosed the presence of drugs—am�tr�ptyl�ne, barb�turate, chloroqu�ne, chlorpromaz�ne, morph�ne, perphenaz�ne, phen�ram�ne, and qu�n�d�ne—�n 7 p�lots (255). A summary of tox�colog�cal find�ngs of fatal gen-eral av�at�on acc�dents (October 1968–September 1974) suggested the presence of drugs �n 16 of 1,345 fatal�t�es (165). In another study (166), the use of drugs has been reported to be less �n agr�cultural p�lots (1.1% of 174) than �n general av�at�on p�lots (4.9% of 2,449) dur�ng the per�od of 1973–1977. Tox�colog�cal evaluat�ons of samples from 377 av�at�on fatal�t�es dur�ng October 1988 to September 1989 concluded that 12.6% of the cases were pos�t�ve for 1 or more drugs (161). Cannab�no�ds were found �n 1.3% of the cases and benzoylecgon�ne �n 1.6%. Acetam�nophen and sal�cylate were the most frequently encountered drugs. Includ�ng chloroqu�ne and n�cot�ne, over-the-counter analges�cs, ant�h�stam�n�cs, and sympathom�met�cs have been �dent�fied �n m�l�tary a�rcraft fatal�ty cases from 1986 to 1990 (159).
Between 1989 and 1993, postmortem samples from 1,845 p�lots were tox�colog�cally analyzed at CAMI (35). Controlled dangerous substances of Schedules I and II (amphetam�ne/methamphetam�ne, barb�turates, coca�ne, code�ne/morph�ne, mar�huana, methaqualone, phencycl�-d�ne, and synthet�c op�ates) were found �n 74 p�lots and of Schedules III–V (benzod�azep�nes, phend�metraz�ne, and phenterm�ne) �n 28 [for the class�ficat�on of Sched-uled substances, see ref. (47)]. Prescr�pt�on drugs were found �n 110 p�lots, over-the-counter drugs �n 207, and ethanol �n 146. Analyses of postmortem samples from 1,683 p�lots dur�ng 1994 to 1998 d�sclosed the pres-ence of controlled dangerous substances of Schedules I
22
and II (amphetam�ne/methamphetam�ne, barb�turates, coca�ne, code�ne/morph�ne, mar�huana, methaqualone, phencycl�d�ne, and synthet�c op�ates) �n 89 p�lots and of Schedules III–V (benzod�azep�nes, fenfluram�ne, pentazo-c�ne, phend�metraz�ne, phenterm�ne, propoxyphene/nor-propoxyphene) �n 49 p�lots (40, 41). Prescr�pt�on drugs were detected �n 240 p�lots, over-the-counter med�cat�ons �n 301, and ethanol �n 124. In cont�nuat�on of these 2 preced�ng stud�es (35, 40, 41), an ep�dem�olog�cal as-sessment was made for an add�t�onal per�od of 5 years (1999–2003) (58, 59). Of 1,629 fatal av�at�on acc�dents from wh�ch CAMI rece�ved b�osamples, there were 1,587 acc�dents where�n p�lots were fatally �njured. Drugs and/or ethanol were found �n 830 of the 1,587 fatal�t�es. Controlled substances of Schedules I and II (amphet-am�ne/methamphetam�ne, barb�turates, coca�ne and �ts metabol�te(s), code�ne/morph�ne, mar�huana, 3,4-methy-lened�xoymethamphetam�ne, and synthet�c op�ates) and of Schedules III–V (benzod�azep�nes, phenterm�ne, propoxyphene/norpropoxyphene, and zolp�dem) were detected �n 113 and 42 p�lots, respect�vely. Prescr�pt�on drugs were present �n 315 p�lots, nonprescr�pt�on drugs �n 259, and ethanol �n 101. More than 1 drug was present �n some fatal�t�es, thus those fatal�t�es were counted more than once—that �s, for each drug or ethanol. Barb�turates �ncluded butalb�tal, pentobarb�tal, and/or phenobarb�tal; mar�huana meant THC and/or THC carboxyl�c ac�d; synthet�c op�ates �nclude hydrocodone, hydromorphone, meper�d�ne, oxycodone, and/or the�r metabol�tes; and benzod�azep�nes enta�led α-hydroxyalprazolam, alpra-zolam, d�azepam, m�dazolam, nord�azepam, oxazepam, and/or temazepam. Prescr�pt�on drugs found �n the 3 stud�es (1989–1993, 1994–1998, and 1999–2003) are tabulated �n Table VII (35, 40, 41, 58, 59). Commonly found non-prescr�pt�on drugs were acetam�nophen, chlorphen�ram�ne, dextromethorphan, doxylam�ne, ephedr�ne, mecl�z�ne, (–)-methamphetam�ne, oxymetazo-l�ne, phenylpropanolam�ne, pseudoephedr�ne, qu�n�ne, sal�cylate, and tr�prol�d�ne. These drugs were pr�mar�ly assoc�ated w�th drug preparat�ons and formulat�ons used to allev�ate allergy and cold symptoms.
Any �ncrease seen �n the prevalence of drugs dur�ng the 15-year per�od (1989–1993, 1994–1998, and 1999–2003) (35, 40, 41, 58, 59) could perhaps be attr�buted to the poss�b�l�t�es of sc�ent�fic and techn�cal advances �n the sens�t�v�ty of analyt�cal methods, genu�ne author�zed med�cal use of such drugs, and/or the�r real abuse. Narcot�c analges�cs found �n p�lot fatal�t�es could have been ad-m�n�stered by emergency health care prov�ders at acc�dent scenes or at hosp�tals for pa�n reduct�on and/or surg�cal procedures. The presence of abused drugs—such as, amphetam�ne/methamphetam�ne, coca�ne, mar�huana, and 3,4-methylened�xoymethamphetam�ne—could have
been assoc�ated w�th the�r unauthor�zed use. Atrop�ne and l�doca�ne m�ght have been adm�n�stered by health care prov�ders for resusc�tat�on. The presence of prescr�pt�on drugs found �n the fatal�t�es reflected the current trends �n the popularly d�spensed groups of med�cat�ons—ant�-hypertens�ves and ant�depressants—�n the U.S. (58, 59). Many of the prescr�pt�on and nonprescr�pt�on drugs, �nclud�ng the controlled substances, present �n the p�lot fatal�t�es have the potent�al for �mpa�r�ng performance, thereby adversely affect�ng the ab�l�ty of an �nd�v�dual to opt�mally p�lot an a�rcraft. F�nd�ngs from these stud-�es support the FAA's programs, �nclud�ng the FAA's drug-test�ng program, a�med at �dent�fy�ng potent�ally �ncapac�tat�ng med�cal cond�t�ons and reduc�ng the usage of performance-�mpa�r�ng drugs or ethanol (49, 102).
4.5.2 SSRIsThe prevalence of SSRIs was evaluated �n p�lot fatal�t�es
of c�v�l av�at�on acc�dents that occurred dur�ng 1990–2001 (5, 6). Of 4,184 fatal c�v�l av�at�on acc�dents, there were 61 acc�dents �n wh�ch p�lot fatal�t�es had SSRIs. Blood concentrat�ons of SSRIs were 11–1,121 ng·ml−1 for fluox-et�ne; 47–13,102 ng·ml−1 for sertral�ne; 68–1,441 ng·ml−1 for paroxet�ne; and 314–462 ng·ml−1 for c�talopram. In 39 p�lots, other drugs—such as, analges�cs, ant�h�stam�n�cs, benzod�azep�nes, narcot�c analges�cs, and/or sympatho-m�met�cs—and/or ethanol were also present. Although blood SSRI concentrat�ons ranged from subtherapeut�c to tox�c levels, the �nteract�ve effects of other drug(s) and ethanol �n produc�ng adverse effects �n the p�lots cannot be ruled out. To establ�sh whether these p�lots had d�s-qual�fy�ng psycholog�cal cond�t�ons, �nclud�ng depress�on, and had properly reported the use of the ant�depressants, the aeromed�cal h�story of these p�lots was exam�ned and reported by Sen et al. (248, 249).
Based upon the d�str�but�on of fluoxet�ne �n 10 fatal av�at�on acc�dent cases, �ts d�str�but�on coeffic�ents, ex-pressed as spec�men type/blood rat�os, were determ�ned to be 0.9 ± 0.4 for ur�ne, 0.10 ± 0.03 for v�treous humor, 9 ± 1 for b�le, 38 ± 10 for l�ver, 60 ± 17 for lung, 9 ± 3 for k�dney, 20 ± 5 for spleen, 2.2 ± 0.3 for muscle, 15 ± 3 for bra�n, and 10 ± 2 for heart (151, 175). Blood concentrat�ons of th�s SSRI �n these fatal�t�es ranged from 21 to 1,480 ng·ml−1.
4.5.3 First-Generation H1 AntihistaminicsAlthough first-generat�on H
1-receptor antagon�sts
cause drows�ness and sedat�on lead�ng to potent�al per-formance �mpa�rment, these ant�h�stam�nes are popularly used for allev�at�ng allergy and cold symptoms. The prevalence of these antagon�sts was evaluated �n p�lot fatal�t�es of c�v�l a�rcraft acc�dents that occurred dur�ng a 16-year (1990–2005) per�od (250, 251). Of 5,383 fatal
23
Table VII. Prescription Drugs Found in Pilot Fatalities
Drugs and Their Metabolites
Aminophenazone Labetalol Amitriptyline/Nortriptyline Lidocaine Amlodipine Maprotiline Atenolol Metoclopramide Atropine Metoprolol Azacyclonol Minoxidil Benzocaine Mirtazapine Bisoprolol Moricizine Brompheniramine Nadolol Bupropion/Metabolite Naproxen Carbamazepine Nizatidine Cetirizine Orphenadrine Chloroquine Pantoprazole Cimetidine Paroxetine Citalopram/Metabolite(s) Phenyltoloxamine Cyclizine Phenytoin Cyclobenzaprine Procainamide/N-Acetylprocainamide Diltiazem Promethazine Diphenhydramine Propoxyphene/Norpropoxyphene Doxazosin Propranolol Doxepin/Nordoxepin Quinidine Etomidate Ranitidine Fenoprofen Sertraline/Desmethylsertraline Fluconazole Sildenafil/Metabolite(s) Fluoxetine/Norfluoxetine Theophylline Gemfibrozil Thiopental Griseofulvin Tramadol Hydrochlorothiazide Trazodone Hydroxyzine Triamterene Ibuprofen Trimethoprim Imipramine/Desipramine Venlafaxine/Desmethylvenlafaxine Ketamine Verapamil/Norverapamil
24
av�at�on acc�dents, there were 338 acc�dents where�n p�lot fatal�t�es (cases) were found to conta�n bromphen�ram�ne, chlorphen�ram�ne, d�phenhydram�ne, doxylam�ne, phe-n�ram�ne, phenyltoloxam�ne, promethaz�ne, and tr�pro-l�d�ne. Ant�h�stam�nes were detected alone �n 103 fatal�t�es, wh�le other drug(s) and/or ethanol were also present �n an add�t�onal 235 fatal�t�es. More than 1 ant�h�stam�ne was detected �n 35 fatal�t�es. Although blood was not ava�lable for analyses �n all cases, blood concentrat�ons (ng·ml−1) were: 5–200 (n = 8) for bromphen�ram�ne; 4–6,114 (n = 67) for chlorphen�ram�ne; 9–3,800 (n = 125) for d�-phenhydram�ne; 10–1,309 (n = 33) for doxylam�ne; and 4 (n = 1) for phenyltoloxam�ne. These levels were �n the sub-therapeut�c to tox�c range. In an earl�er study (262), 47 (2.2%) acc�dents that occurred dur�ng 1991–1996 were assoc�ated w�th chlorphen�ram�ne. Related to these acc�dents, 16 p�lots had only chlorphen�ram�ne at 109 ng·ml−1 (n = 4) �n blood and 1,412 ng·g−1 (n = 12) �n l�ver. Other drugs were also present �n the rema�n�ng cases, where�n chlorphen�ram�ne concentrat�ons were 93 ng·ml−1 (n = 18) �n blood and 747 ng·g−1 (n = 12) �n l�ver. N�nety-five percent of all quant�tated blood values were at or above the therapeut�c level (10 ng·ml−1).
4.5.4 Other Drugs4.5.4.1 Selegiline
Stereochem�cal determ�nat�on of seleg�l�ne metabol�tes �n postmortem b�olog�cal spec�mens from an av�at�on acc�dent p�lot fatal�ty was accompl�shed to deduce that the p�lot was be�ng treated for Park�nson’s d�sease (164). Such analyt�cal d�fferent�at�on between dextrorotatory and levorotatory methamphetam�ne/amphetam�ne has been appl�ed to establ�sh the opt�cal pur�ty of methamphet-am�ne found �n tox�c concentrat�on �n a fatally �njured p�lot of an av�at�on acc�dent (57).
4.5.4.2 SildenafilConcentrat�ons of s�ldenafil and �ts act�ve metabol�te
have been reported �n var�ous b�olog�cal samples from v�ct�ms from 6 separate av�at�on fatal�t�es (150, 173).
4.5.4.3 VardenafilThe postmortem d�str�but�on of vardenafil, w�th an
unusually h�gh blood concentrat�on, has been evaluated �n an av�at�on acc�dent v�ct�m (152).
4.5.4.4 ButalbitalIn an attempt to est�mate blood butalb�tal concentra-
t�ons from the drug levels �n ava�lable t�ssues, d�str�bu-t�on of butalb�tal was stud�ed �n var�ous postmortem t�ssues and flu�ds from av�at�on acc�dent fatal�t�es (176). The d�str�but�on coeffic�ents for butalb�tal, expressed as spec�men type/blood rat�os, were (n = 2–4): 0.66 ± 0.09
for muscle, 0.98 ± 0.09 for k�dney, 0.87 ± 0.06 for lung, 0.75 ± 0.03 for spleen, 0.96 ± 0.07 for bra�n, 2.22 ± 0.04 for l�ver, and 0.91 ± 0.17 for heart.
4.6 Elevated Glucose and HbA1c
V�treous flu�d and ur�ne samples from p�lots fatally �njured �n av�at�on acc�dents are analyzed for glucose and blood for hemoglob�n A
1c (HbA
1c) (19, 36, 37,
291). In an ep�dem�olog�cal study �nvolv�ng 1,335 p�lots (1998–2005), 43 were found to have elevated glucose �n v�treous flu�d ( > 125 mg·dl−1) and/or �n ur�ne (> 100 mg·dl−1). Of the 20 p�lots whose blood samples were analyzed, 9 had > 6% HbA
1c (55). Four of the 9 p�lots
were known d�abet�cs, wh�le 5 were unknown d�abet�cs. A cons�derable number of p�lots (30 of 43) had elevated glucose and HbA
1c (5 of 20), suggest�ng und�agnosed/
unreported d�abet�c cond�t�ons.
5 CABIN AIR CONTAMINATION
5.1 Introductory AspectsQual�ty of a�r �n cab�ns of a�rcraft has been a top�c of
debate and d�scuss�on s�nce at least the 1970s. Aerospace a�r pollut�on �ssues—that �s, cab�n a�r qual�ty of a�rcraft and space veh�cles—have been succ�nctly addressed �n an art�cle by Patterson and Rayman (210). These �ssues are �n v�ew of the facts that the crews must work, sleep, and l�ve �n the cab�n env�ronments of a�rcraft and space veh�cles. Throughout the world, the poss�ble adverse ef-fects of cab�n atmosphere contents on the health of a�r crews and travelers have been evaluated (30, 31, 122, 134, 217, 218, 220, 285, 300). A�rcraft cab�n a�r qual�ty- related b�lls �n the U.S. Congress and reports of the U.S. Nat�onal Academy of Sc�ences have been �n the l�mel�ght �n the field of aerospace med�c�ne (217, 218, 221). More than 30 years ago, the qual�ty of cab�n a�r was apparently not an �ssue �n commerc�al av�at�on, and the �nc�dence of d�sease through a�rborne vectors or tox�c fumes was uncommon (3). However, modern jet a�rl�ners may have the threat of d�sease because the�r vent�lator systems are des�gned for opt�mum effic�ency, leav�ng them exposed to lapses �n the recycl�ng of clean a�r and block�ng fumes from jet eng�ne exhausts from enter�ng the a�rcraft cab�n areas. Aero-tox�c fumes are most common �n the cockp�t, and the crew members are the most suscept�ble to the aero-tox�c syndrome (3). In a comprehens�ve rev�ew of 21 stud�es exam�n�ng the effect of the a�rl�ner cab�n env�ron-ment and other factors on the health and comfort of fl�ght attendants, Nagda and Koontz (197) found that var�ous compla�nts and symptoms reported by the attendants appeared to be assoc�ated w�th the�r job dut�es and w�th the cab�n env�ronment. The “dryness” symptoms were attr�butable to low hum�d�ty and “fat�gue” symptoms w�th
25
factors such as d�srupt�on of c�rcad�an rhythm. Certa�n fl�ght attendants compla�nts were cons�stent w�th poss�ble exposure to a�r pollutants, but that relat�onsh�p has not been establ�shed w�th a v�ew that such compla�nts also were cons�stent w�th causes other than poor a�r qual�ty. In sp�te of health �ssues assoc�ated w�th a�r travel, there are enormous benefits to travelers, to commerce, to �n-ternat�onal affa�rs, and to health (96).
Stresses, l�ke a�rport tumult, barometr�c pressure changes, �mmob�l�ty, jet lag (238), no�se, v�brat�on, and rad�at�on, �mposed by commerc�al fl�ghts upon travelers and �n-fl�ght �llness and med�cal care capab�l�ty aboard U.S. a�r carr�ers have been addressed �n a rev�ew art�cle (219). S�nce the “cab�n a�r qual�ty” top�c has been of concern and controversy, the Aerospace Med�cal Asso-c�at�on (AsMA) has rev�ewed the sc�ent�fically accepted facts �n the d�fferent elements (such as pressur�zat�on, vent�lat�on, contam�nat�on, hum�d�ty, and temperature) assoc�ated w�th a�rcraft cab�n atmospheres (270). AsMA recommended that regulators, a�rl�nes, and sc�ent�fic as-soc�at�ons work together on the �ssue of cab�n a�r qual�ty because no amount of techn�cal data alone would solve the problem. A�rcraft cab�n CO
2 concentrat�ons calculated
from the publ�shed vent�lat�on rat�ngs were found to be �ntermed�ate to these sets of results obta�ned by actual measurement. These find�ngs are used to arr�ve at recom-mendat�ons for a�rcraft bu�lders and operators to help �mprove a�rcraft cab�n a�r qual�ty at m�n�mum cost (145). Based on the passenger a�rcraft cab�n a�r qual�ty cover�ng trends, effects, soc�etal costs, and proposals, suggest�ons for a�r qual�ty �mprovement were made result�ng �n a net, mult�-stakeholder sav�ngs and �mproved passenger comfort (146). Av�at�on �ndustry and passenger perspec-t�ves �n relat�on to cab�n a�r qual�ty have been evaluated by Hock�ng (147). Accord�ngly, recommendat�ons and suggest�ons were made for a�rcraft bu�lders, operators, and passengers. Those recommendat�ons/suggest�ons would help �mprove a�rcraft cab�n a�r qual�ty and the part�al pressure of oxygen that �s ava�lable to passengers at m�n�mal cost and enhance the�r comfort and decrease the�r r�sk of �llness. In an overv�ew by Rayman (221), recom-mendat�ons have been made on how the cab�n a�r qual�ty �ssue may be resolved. Furthermore, a l�terature rev�ew demonstrated that a�rl�ner cab�n a�r qual�ty �s adequate and does not comprom�se a�rcrew health (271), though the need for further stud�es was acknowledged.
5.2 Aircraft Cabin Air Fat�gue �n a�rcrew members perform�ng frequent and
long-range fl�ghts has been l�nked to a�rcraft-related no�se, temperature, cab�n pressure, vent�lat�on, atmosphere qual�ty, hum�d�ty, jet lag, and fl�ght character�st�cs (122, 285). Vent�lat�on adequacy, c�garette fires, and p�lot
health �ssues have been addressed (122). Presence of less fresh a�r �n cab�n was acknowledged, but there was more than enough oxygen for human consumpt�on (134). The concentrat�on of m�croorgan�sms �n a�rl�ne cab�n a�r was found to be much lower than the�r concentrat�on �n ord�nary c�ty locat�ons (292), conclud�ng that the small number of m�croorgan�sms found �n the U.S. a�rl�ner cab�n env�ronments does not contr�bute to the r�sk of d�sease transm�ss�on among passengers. In a 1997 study of A�rbus a�rcraft (95), the number of part�cles �n cab�n a�r was compared w�th fresh a�r and re-c�rculated a�r. Also, m�crob�olog�cal contam�nat�on and volat�le organ�c compound concentrat�ons �n cab�ns were �nvest�gated. The part�cles were found to be ma�nly em�tted by pas-sengers, espec�ally smokers, and the rec�rculat�on a�r conta�ned a lower or equal amount of part�cles compared to the fresh a�r, whereas the amount of bacter�a exceeded reported concentrat�ons w�th�n other �ndoor spaces. The detected m�crobes were ma�nly non-pathogen�c, and the concentrat�ons of volat�le organ�c compounds were well below threshold values. Modern h�gh effic�ency part�culate a�r (HEPA)-filters m�n�m�ze an accumulat�on of bacter�a and v�ruses w�th�n the rec�rculat�on flow of the cab�n a�r, thereby s�gn�ficantly reduc�ng the overall r�sk of gett�ng �nfect�ous d�seases, compared w�th other means of transportat�on (20). The �ssue of the fly�ng fitness of pat�ents w�th �nfect�ons has been d�scussed (132). Cargo, as well as passenger, a�rcrafts have proven to be vectors of d�sease because they transport humans, mosqu�toes, other �nsects, and an�mals (96). The oc-currence of transm�ss�on of tuberculos�s and �nfluenza to other travelers has been reported, and vectors for yellow fever, malar�a, and dengue have been �dent�fied on a�rcraft. However, stud�es of vent�lat�on systems and pat�ent outcomes suggest that the spread of pathogens occurs rarely dur�ng fl�ghts (169).
A rev�ew of reported a�r concentrat�ons of organ�c compounds �n cab�ns �nd�cated that contam�nant levels �n a�rcraft cab�ns are s�m�lar to those �n res�dent�al and office bu�ld�ngs (198). However, there were 2 except�ons. F�rst, levels of ethanol and acetone—�nd�cators of b�o-effluents and chem�cals from consumer products—were h�gher �n a�rcraft than �n home or office env�ronments and �n other transportat�on modes; second, levels of certa�n chlor�nated hydrocarbons and fuel-related contam�nants were h�gher �n res�dent�al/office bu�ld�ngs than �n a�rcraft. The levels of chem�cals such as m- and/or p-xylenes tend to be lower �n a�rcraft. Although cab�n a�r �s filtered pr�or to rec�rcula-t�on to remove volat�le organ�c compounds and odor by us�ng adsorbers, such dev�ces may not be �nstalled �n all a�rcraft and may not be capable of remov�ng all pollut-ants. Therefore, the photo-catalyt�c a�r filter�ng approach was developed, and �t seems prom�s�ng to resolve odor
26
problems �n a�rcraft (127). The overall effic�ency of the photo-catalyt�c un�t �s the funct�on of the character�st�cs of compounds (toluene, ethanol, and acetone) that challenge the un�t. Toluene was apparently found to be the most d�fficult compound to be ox�d�zed. The photo-catalyt�c techn�que used by the tested prototype un�t �s able to part�ally ox�d�ze volat�le organ�c compounds, but one has to be aware that some tox�c �ntermed�ate chem�cal react�on products such as formaldehyde and acetaldehyde are also produced dur�ng the ox�dat�on process.
H�gh concentrat�ons of ozone can lead to upper resp�ratory problems and of CO
2 may cause hyperven-
t�lat�on (20). Add�t�onally, the mucous membranes of the resp�ratory tract are dr�ed out due to the extremely low hum�d�ty of the cab�n a�r. In a 2000 study by Back-man and Hagh�ghat (9), h�gh CO
2 concentrat�ons and
low hum�d�ty levels were found �n the A�rbus 320. The h�ghest hum�d�ty level was determ�ned �n the DC-9; the lowest CO
2 concentrat�on �n the Boe�ng 767. The authors
concluded that poor a�r qual�ty may cause �ntolerance to contact lenses, dry eyes, and may be a health hazard to both passengers and crew members. In the U.S. A�r Force C-5 cab�n a�r, CO and CO
2 concentrat�ons were
found to be well below health effect threshold, relat�ve hum�d�ty a lowest level of 3%, and ozone at relat�vely low concentrat�ons (141). The �nfluence of ozone on self-evaluat�on of symptoms �n a s�mulated a�rcraft cab�n �nd�cated that the a�r qual�ty and 12 of the symptoms, �nclud�ng eye and nasal �rr�tat�on, l�p and sk�n dryness, headache, d�zz�ness, mental tens�on, and claustrophob�a, were establ�shed to be s�gn�ficantly worse (p < 0.05) for the “ozone” cond�t�on, compared to the “no ozone” cond�t�on (265).
Dur�ng �ntercont�nental fl�ghts (180), CO2 levels were
below 1,000 ppm �n 97% of the cases and hum�d�ty was very low (5%). Low hum�d�ty m�ght conce�vably be a factor for mucosal �rr�tat�on exper�enced by travelers and fl�ght attendants �n a�rcraft cab�ns (178, 196, 280), and tobacco-smok�ng onboard m�ght contr�bute to s�gn�fi-cant pollut�on from resp�rable dust (178, 180, 294). An �nvest�gat�on on the �nfluence of a�r hum�d�ficat�on on �ntercont�nental fl�ghts on the percept�on of cab�n a�r qual-�ty among a�rl�ne crew concluded that relat�ve hum�d�ty can be sl�ghtly �ncreased by us�ng a ceram�c evaporat�on hum�d�fier, w�thout any measurable �ncrease of m�croor-gan�sms (181). The evaluat�on of the opt�mum balance between fresh a�r supply and hum�d�ty from 7-h exposures �n a s�mulated a�rcraft cab�n exh�b�ted that �ncreas�ng the relat�ve hum�d�ty �n the cab�n to 28% by reduc�ng outs�de flow to 1.4 l·s−1 per person d�d not reduce the �ntens�ty of the symptoms that are typ�cal of the a�rcraft cab�n env�ronment. However, th�s adjustment �ntens�fied
compla�nts of headache, d�zz�ness, and claustrophob�a, due to the �ncreased level of contam�nants (266).
The assessment of the contr�but�on of secondhand smoke to a�rcraft cab�n a�r pollut�on and fl�ght attendants has been made relat�ve to the general populat�on and was determ�ned that vent�lat�on systems mass�vely fa�led to control secondhand smoke a�r pollut�on �n cab�ns (224). However, smok�ng �s now proh�b�ted by most a�rl�nes and a�r pollut�on caused by smok�ng �s no longer a relevant �ssue. Add�t�onal stud�es further emphas�ze that the relat�ve a�r hum�d�ty was very low on �ntercont�nental fl�ghts, and part�cle levels were h�gh on fl�ghts w�th pass�ve smok�ng (179). These find�ngs suggested the need for �mprov�ng cab�n a�r qual�ty by better control of cab�n temperature, a�r hum�d�ficat�on, a�r filtrat�on (HEPA filters), and suf-fic�ent a�r exchange rate on all a�rcraft types.
5.3 Space Vehicle Cabin AirAstronauts work, sleep, and l�ve �n space veh�cles (210),
and there �s a strong potent�al for the slow and �ns�d�ous bu�ldup of tox�c substances—such as refr�gerants, CO, HCN, CO
2, ammon�a, and other organ�c compounds—�n
the space veh�cle cab�n atmosphere. Tox�c substances could also be released rap�dly �n h�gh concentrat�ons. The sources of these substances could be from off-gass�ng, human metabol�sm, payload chem�cals, and thermal degradat�on of mater�als. Therefore, the protect�on of the astronauts’ health and the prevent�on �n the�r performance decre-ments are cruc�al. A major concern �n the space cab�n �s the establ�shment of max�mum allowable concentrat�ons of potent�ally tox�c substances. Such establ�shment should be based upon the facts that astronauts l�ve �n a closed env�ronment of space veh�cles 24 h a day, for weeks or even months, �n compar�son to an 8-h work�ng sh�ft on the Earth. Contract�ng m�crobes �n the space cab�n �s of concern s�nce crew members would release many bacter�a �nto the env�ronment, and the�r droplets �n m�crograv�ty rema�n suspended �n the atmosphere, thus mak�ng the�r exposures more l�kely. How m�crograv�ty affects the �m-mune system of humans has not been well-establ�shed. Therefore, the mon�tor�ng of m�croorgan�sms and tox�c substances �s cruc�al �n the space veh�cle cab�n atmosphere. Methods and means of qual�tat�ve and quant�tat�ve a�r mon�tor�ng on the Internat�onal Space Stat�on are suf-fic�ent for a�r control �n emergency s�tuat�ons such as local fire and tox�c leak. Also, the Stat�on’s a�r qual�ty has su�ted to the adopted standards and crew safety requ�rements. However, there �s a need to �mprove the space cab�n a�r mon�tor�ng (208).
In the area of mon�tor�ng, the development of mass spectrometry �nstrumentat�on to support the goals of the U.S. space program (209) has taken place for study�ng the
27
compos�t�on of planetary atmospheres and mon�tor�ng a�r qual�ty on manned space m�ss�ons. The mass spectrometry �nstruments deployed on the P�oneer Venus and the Mars V�k�ng Lander m�ss�ons have been rev�ewed for �llustrat�ng the un�que features of the sample �ntroduct�on systems, mass analyzers, and vacuum systems, and for present�ng the�r spec�ficat�ons. Var�ous approaches for mon�tor�ng volat�le organ�c compounds �n cab�n atmospheres were also rev�ewed. Prev�ously, ground-based gas chromatog-raphy-mass spectrometry �nstruments have been used to �dent�fy and quant�fy volat�le organ�c compounds �n arch�val samples collected dur�ng the Mercury, Apollo, Skylab, Space Shuttle, and M�r m�ss�ons. The develop-ment of d�rect sampl�ng �on trap mass spectrometry and gas chromatography-�on mob�l�ty spectrometry has been d�scussed to �llustrate the�r potent�al ut�l�ty for future m�s-s�ons. A m�n�ature electron�c nose has been des�gned and bu�lt at the Jet Propuls�on Laboratory (Pasadena, CA) to detect, �dent�fy, and quant�fy 10 common contam�nants and relat�ve hum�d�ty changes (232). The sens�ng array �ncluded 32 sens�ng films composed of polymer carbon-black compos�tes. Event �dent�ficat�on and quant�ficat�on were done us�ng the Levenberg-Marquart nonl�near least squares method. Th�s electron�c nose was used �n a demon-strat�on exper�ment aboard STS-95 (October-November, 1998) (277), �n wh�ch the electron�c nose was operated cont�nuously for 6 d and recorded the responses of the sensors to the a�r �n the m�d-deck. A�r samples were col-lected da�ly and analyzed �ndependently after the fl�ght. Changes �n shuttle-cab�n hum�d�ty were detected and quant�fied by the electron�c nose. Th�s dev�ce was found to be m�crograv�ty-�nsens�t�ve.
5.4 Aircraft Engine Oils, Hydraulic Fluids, and Lubricants
Many �nc�dents of smoke/fumes �n a�rcraft cab�ns have been l�nked to contam�nat�on of cab�n a�r w�th pyrolyt�c products of jet eng�ne o�ls, hydraul�c flu�ds, and/or lubr�cants by leak�ng �nto vent�lat�on a�r (84, 235, 281, 283). These leaks can be subjected to 500°C or h�gher temperatures. If the or�g�n of the smoke/fumes �s of organ�c petroleum der�vat�ves, then the smoke/fumes may cause a mult�tude of symptoms, �nclud�ng central nervous system dysfunct�on and mucous membrane �rr�ta-t�on. There �s a threat to safety posed by the many flu�ds and substances necessary for the operat�on of modern a�rcraft (222). Smoke/fume-related �nc�dents could have been caused by broken seals �n the eng�ne and/or other assoc�ated systems, allow�ng these eng�ne agents to enter the a�r compressor sect�on and, then, contam�nate the cab�n a�r. To prevent such products from enter�ng the cab�n a�r, catalyt�c converters have been used to clean the a�r (282), but dur�ng an o�l seal fa�lure, the converters
become overloaded, and smoke could be observed �n the cab�n. In some a�rcraft, the catalyt�c converters have been removed, w�th a cla�m that �t �mproves cab�n a�r qual�ty. However, �f the cab�n a�r �s contam�nated, the fl�ght crew �s potent�ally exposed to the thermal breakdown products of the eng�ne agents, caus�ng the performance of the crew members to be �mpa�red. Symptoms, l�ke d�zz�ness, nausea, d�sor�entat�on, blurred v�s�on, and t�ngl�ng �n legs and arms, have frequently been reported by fl�ght crews. The reported symptoms are most cons�stent w�th exposures to CO and pyrolyt�c products, �nclud�ng volat�le organ�c compounds and the organophosphate const�tuents of the o�ls and flu�ds, but the �nvolvement of these l�qu�ds has not been clearly demonstrated (281). In th�s 1999 study (281), to rule out the poss�ble exposure to tox�c elements, l�ke lead, mercury, and thall�um, a mult�-el-emental analys�s was performed on 2 hydraul�c flu�ds and 3 lubr�cat�ng o�ls that have been �mpl�cated �n a number of a�r qual�ty �nc�dents. No s�gn�ficant concentrat�ons of the tox�c elements were found �n any of the o�ls or hydraul�c flu�ds.
In m�d-1981, several acc�dents �nvolv�ng turboprop a�rcraft occurred. It was bel�eved that those acc�dents resulted from p�lot �ncapac�tat�on from tox�c fumes �ntroduced through the cab�n pressur�zat�on system (235). Therefore, the thermal (300–600°C) decompo-s�t�on products from a�rcraft petroleum-based eng�ne and synthet�c lubr�cat�ng o�ls were evaluated for the�r tox�c�ty �n rats (84). The an�mals were exposed to smoke from these products, and relat�ve tox�c�ty was evaluated �n terms of t
� and t
d. The CO concentrat�ons �n smoke
were measured. Based on th�s �nformat�on, �n conjunc-t�on w�th the an�mal response t�mes, �t was concluded that the decompos�t�on of these o�ls d�d not produce any chem�cal spec�es, other than CO, �n quant�t�es suffic�ent to contr�bute to the total tox�c�ty.
S�nce bleed a�r �s d�verted from a locat�on just pr�or to the eng�ne combust�on chamber at a temperature around 500°C and very l�ttle �s known regard�ng the thermal breakdown products of jet eng�ne lubr�cat�on o�ls, 2 com-merc�ally ava�lable o�ls were �nvest�gated under laboratory cond�t�ons at 525°C to measure the release of CO, CO
2,
n�trogen d�ox�de, HCN, and volat�les (282). The volat�les were analyzed by gas chromatography-mass spectrometry to establ�sh �f the neurotox�c agents, tr�cresyl phosphates (TCPs) and tr�methyl propane phosphate (TMPP), were present or formed �n the release. Although some CO
2
was generated, along w�th CO (> 100 ppm), n�trogen d�ox�de and HCN were not detected under the analyt�-cal cond�t�ons. The presence of TCPs was confirmed �n the bulk o�ls and �n the volat�les, but TMPP was not found �n these exper�ments. Local�zed condensat�on �n the vent�lat�on ducts and filters �n the a�r cond�t�on�ng
28
packs are l�kely the reasons for the absence of TCPs �n cab�n a�r. However, the poss�b�l�ty of the release of py-rolys�s products cannot be ruled out from the local�zed condensates �n the ducts at the t�me of h�gh demand of cab�n heat, lead�ng to m�d-fl�ght �nc�dents (283).
The Un�ted K�ngdom’s C�v�l Av�at�on Author�ty (33) conducted an extens�ve study on cab�n a�r qual�ty �nvolv-�ng o�ls and flu�ds. Th�s study exam�ned and analyzed 2 contam�nated cab�n a�r supply ducts for the presence of chem�cal const�tuents and degradat�on products of eng�ne o�ls, hydraul�c flu�ds, and lubr�cants. These ducts were removed from 2 a�rcraft, where�n the �nner surface of the ducts was found to be coated w�th black part�culate mater�al. M�croscop�c exam�nat�on of th�s carbonaceous mater�al determ�ned that �t was r�ch �n var�ous elements, such as alum�num, s�l�con, sulfur, and phosphorous. These black mater�al depos�ts can be eas�ly d�slodged by gentle pressure. Thus, the mater�al could potent�ally become part of the cab�n and fl�ght deck env�ronment as sol�d aerosols. The gas chromatograph�c-mass spectrometr�c analyses of the a�rflow samples of the contam�nated ducts suggested the presence of var�ous short cha�n �r-r�tants, such as carboxyl�c ac�ds, aldehydes, and ketones. Analyses of the solvent extracts of the carbonaceous mater�al further �nd�cated the presence of add�t�onal h�gh molecular we�ght chem�cals—for example, TCPs, TMPP, tr�methylolpropane phosphates, and other as-soc�ated esters—of relat�vely low volat�l�ty. It appeared that these molecules m�ght have been t�ghtly �ntegrated to the carbonaceous mater�al, suggest�ng that not all of the chem�cals adsorbed onto the carbonaceous mater�al could be desorbed by a�rflow.
It �s true that the a�rflow samples d�d not conta�n all the chem�cals present �n the black sol�d coat�ng of the ducts, but �t does not necessar�ly mean that only those chem�cals found �n the a�rflow samples are respons�ble for the observed tox�colog�cal effects. Other chem�cal ent�t�es adsorbed onto the sol�d mater�al could also contr�bute to the tox�c�ty, �f the sol�d mater�al part�cles become part of the a�r. There �s a strong potent�al for th�s type of s�tuat�on, because the black part�culate mater�al present �n the ducts can eas�ly be d�slodged by apply�ng gentle pressure. The d�slodg�ng could also take place at t�mes of h�gh demand of cab�n heat and/or by phys�cal d�sturbances and/or stresses occurr�ng dur�ng fl�ghts, part�cularly dur�ng tak�ng off and land�ng. The ease of d�slodg�ng of part�culate matter would also be dependent upon the amount of the sol�d matter coated �ns�de the ducts—larger the s�ze of the depos�ts, eas�er the d�slodg-�ng of the depos�ts as the carbonaceous mater�al part�cles would be loosely bound �n the larger depos�ts. Hence, those sol�d part�cles could eas�ly become part of the cab�n and fl�ght deck env�ronment as sol�d aerosols.
In such scenar�os, �f the cab�n and fl�ght deck occu-pants �nhale those part�cles, they would be exposed to all the chem�cals and assoc�ated ent�t�es present �n the a�rflow from the ducts, as well as �n the sol�d depos�ts of the ducts. Th�s exposure to the m�xture of chem�cals would cause a spectrum of adverse effects—for example, ocular and upper resp�ratory �rr�tat�on, nausea, vom�t�ng, d�zz�ness, pulmonary tox�c�ty, and even delayed adverse effects. In th�s way, the sol�d part�cles would actually be more effect�ve �n produc�ng local�zed adverse effects. The nature and extent of such effects would, of course, be dependent upon the types and amounts of chem�cals present �n the a�r and the durat�on and frequency of such exposures, and these parameters would vary from fl�ght to fl�ght. Therefore, the whole ep�sode �s a complex set of events. Also, �t �s not so s�mple to adjud�cate and pred�ct the tox�c�ty caused by the const�tuents and the pyrolyt�c products of eng�ne o�l, hydraul�c flu�ds, and lubr�cants.
In the C�v�l Av�at�on Author�ty study (33), the smell of the a�rflow samples was subject�vely character�zed for the odor. Th�s qual�tat�ve approach reconfirmed that the odor or�g�nated from the carbonaceous mater�al. However, as d�scussed �n the report, the �nterrelat�onsh�p cannot be establ�shed between the odor and the tox�c�ty of a chem�cal. For example, some chem�cals produce odor at very low concentrat�ons w�thout caus�ng tox�c�ty, whereas some chem�cals have no odor but are extremely tox�c. Tox�c�ty of the var�ous substances found �n the carbona-ceous mater�al �s descr�bed and d�scussed �n deta�l w�th suffic�ent relevant sc�ent�fic references. However, �t appears from the report that the descr�bed tox�c�ty �s the tox�c�ty exh�b�ted by �nd�v�dual chem�cal ent�t�es. The resultant of the tox�c�ty of all of the chem�cals present �n the black sol�d mater�al �s not clearly ev�dent. Th�s aspect �s of par-t�cular �mportance, as a�rcraft travelers would potent�ally be exposed to chem�cals, not a s�ngle chem�cal, from the black mater�al. It �s well establ�shed that the tox�c�ty of �nd�v�dual substances d�ffer from the�r m�xture(s). Such d�fference would be because of the �nteract�ve effects of chem�cals present �n the m�xture(s). Thus, the overall tox�c�ty would be the result of add�t�ve, potent�at�on, synerg�st�c, and/or antagon�st�c type of �nteract�on(s) among chem�cals present �n the m�xtures �n relat�on to the tox�c effects exerted by the �nd�v�dual components of the chem�cal m�xtures (106). In other words, the chem�cals found �n the carbonaceous mater�al may not necessar�ly be �nd�v�dually tox�c at the found concentrat�ons, but �f they are m�xed together at those concentrat�ons, the m�xture m�ght be h�ghly tox�c. Interact�on of chem�cals would also play a cruc�al role �n exh�b�t�ng character�st�c odor, wh�ch may not necessar�ly be cons�stent w�th the odor exh�b�ted by an �nd�v�dual chem�cal �tself. The �ssue of the �nteract�on of chem�cals �n regard to the tox�c�ty of
29
m�xtures has apparently not been fully addressed or em-phas�zed �n the report. Because of the complex�ty, the best approach to resolve th�s tox�colog�cal and av�at�on safety �ssue would be prevent�ve (33)—that �s, to m�n�m�ze o�l leaks �nto bleed a�r and to mon�tor, clean, and/or replace a�r ducts. The tox�c�ty of the o�l add�t�ves that are used �n a�rcraft eng�nes should also be rev�s�ted (202).
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FURTHER READING
Brunton LL, Lazo JS, Parker KL, Eds, Goodman & G�lman’s the pharmacolog�cal bas�s of therapeut�cs, 11th ed; McGraw-H�ll, New York, NY; 2006.
Dav�s JR, Johnson R, Stepanek J, Fogarty JA, Eds, Fundamentals of Aerospace Med�c�ne, 4th ed; L�pp�ncott W�ll�ams & W�lk�ns, Ph�ladelph�a, PA; 2008.
Klaassen CD, Ed�tor, Casarett & Doull’s tox�cology: The bas�c sc�ence of po�sons, 7th ed; McGraw-H�ll, New York, NY; 2008.
Ra�nford DJ, Gradwell DP, Eds, Ernst�ng’s av�at�on med�c�ne, 4th ed; Hodder Arnold, London, UK; 2006.
