Limitations of Current Toxicity Testing for

Identifying Early Life Stage Susceptibilities

Gary Ginsberg

Connecticut Dept of Public Health

NE SRA Regional Chapter

June 19, 2007

Introduction

• Children are not a single receptor group– Broad range of developmental stages and

exposure characteristics– Critical windows of development

• Cancer risk high early post-natal, pubertal• Lung development- opportunities for physiologic

impairment• Immune development – opps for creating allergic

phenotype• Hormone development – potential impairment of

sexual maturation

Intro (continued)

• Toxicology testing – postnatal not a focus• Epidemiology – children not a focus• Biomonitoring – very little in children• Risk assessment – some focus on children

– Assumed captured in 10x inter-human UF– Cancer RA – no inter-human UF– Children’s soil exposure considered but not

much else

• Implications for RA and Public Health???

Standard Toxicology Testing

• Acute thru chronic testing in young adult rats/mice

• Cancer bioassays – begin in young adults– Newborn mouse model as faster cancer

bioassay ( Fuji, 1991; Flammang, et al., 1997)– Sporadic studies in juvenile rats or mice– Atomic bomb survivors – child risks evaluated– Newborn data analyzed by USEPA and Hattis

Hattis, et al., EHP 113: 509-516, 2005

Neurotoxicity Testing

• Adult rats – std part of subchronic testing • Developmental neurotox

– in utero and postnatal (nursing) exposure – evaluate CNS morphology / behavior in juvenile rats– Trigger – neurotoxic agent

• eg OPs, pyrethroids, perchlorate, metals• Only small percentage of chemicals tested

– USEPA Analysis (Makris, 1998)• NTT is most sensitive in 2 of 9 pesticides

– Limitations: may not involve direct exposure in young • Long-term sequelae not evaluated• Other types of endpoints not evaluated (immunotox, cancer)

Developmental Studies

• Prenatal exposure in pregnant females• Skeletal and visceral abnormalities• No evaluation of post-natal pd• Positive findings relevant for newborns?

– If yes, then what dose response in newborn?– If equal to prenatal, more restrictive stds

• What is relevant post-natal exposure pd

• Negative result – minimal utility for post-natal period

Reproductive Studies

• Std 2 gen: in utero and post-natal (nursing) exposure

• Focus is on reproductive success of offspring

• Limited evaluation of other parameters (e.g. organ wts)

• Nursing only exposure – what dose received by pups?– Will positive factors in milk mask toxic effects?

Reproductive Studies

• If positive, implications for sexual maturation, hormonal/endocrine imprinting,

• If negative, endocrine effects still poss– More subtle maturational/fertility effects

• Rat fertility may not be most sensitive endpoint

– Other endocrine systems may be affected• Thyroid, insulin, corticosteroids

• If positive, typically don’t evaluate windows of vulnerability – Can be key to a risk assessment when pro-rating dose

Toxicity Testing Data Gaps

• Immunotoxicity in general and especially immuntox in early life– Allergic vs. inflammatory phenotype determined early

• Respiratory tract development– Juvenile monkey – ozone/asthma model– Airway changes irreversible – narrowed,

hyperresponsive– Wouldn’t see it in rodents

• Primates have much more lung development postnatal than rodents

• Endocrine – thyroid toxicants – perchlorate• Long-term effects of early life exposures

Toxicokinetics for Early Life

• TK studies not done in juvenile animals • TK in children understood from therapeutic

drugs• PBTK models can simulate internal dose in

children• Novel pathways/metabolites can exist at

immature stages of development • Children’s TK not considered in most RA

Unique Exposure Pathways in Early Life

• Very early ages not well addressed– Breast milk– Reconstituted formula

• House dust– Pesticides– PFOA– PBDEs– Lead

Biomonitoring in Early Life

• Lead – all children screened

• NHANES – Pb, Hg, Cd only

• Blood bank study – youngest ages have highest blood PFOA

• Newer methods – diaper analyses

Can RA Do a Good Job on Kids?

• Children – – highly variable exposure, important TK

variability, critical stages of vulnerability• Juvenile animals – more sensitive to

carcinogens, pesticides• Very little epidemiology, biomonitoring• Toxicity testing gaps – compounds

uncertainty

Implications for RA

• Standard UFs – may not capture inter-individual and datagaps in child database

• Logic to FQPA 10x children’s UF• Factors to capture greater exposure/minimal

chronic pd (2-5x), and greater carcinogen sensitivity (2x) are minimal adjustments

• Children/juvenile life stages need to receive greater focus in future of tox testing

• New NAS report on Tox Testing – Concerned with life stages– Major view towards upstream testing, hi thruput,

omics