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Stephen J. GenuisMD FRCSC DABOG DABEM FAAEM

Clinical Professor

University of Alberta

Occupational and Environmental Medical

Association of Canada

34th Annual Scientific Conference

Sept 2016

Dr. Stephen J Genuis

� Relationship with commercial interests – None

� Disclosure of Commercial Support – None

� Mitigating Potential Bias – None

� Conflict of interest – None

� Consulting Fees – None

� Grants/Research Support – None

� Speakers Bureau/Honoraria - None

Learning Objectives:

1. Recognize the emerging area and relevance of Environmental Medicine.

2. Introduce an Environmental Health clinical approach to assisting patients with

varied types of illness.

3. Consider some of the challenges faced by Environmental Medicine practitioners.

4. Describe emerging pathophysiological mechanisms for the increasing

phenomena of inexplicable multimorbidity & sensitivities, and introduce a clinical

approach to assist patients with such problems.

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I. Background & Context (Why is EM relevant?)

II. Approach to clinical practice of EM & the challenges

III. Origins of a common EM presentation: ‘Multimorbidity with Sensitivities’

Canadian Healthcare System:

A fundamental pillar of our national identity

Conference Board of Canada study:

� 90% of Canadians believe that health care should be the main priority for

national decision-makers

� Preserving our healthcare system more important than any other issue

including the economy and the environment

Conference Board of Canada. The inconvenient truths about Canadian Health Care.

http://www.conferenceboard.ca/cashc/research/2012/inconvenient_truths.aspx

219.1 Billion (2015 estimate)

‘Healthcare in Canada is heading toward a fiscal cliff’

^

Rise in costs far exceed

• population growth

• economic growth

• inflation

No signs of slowing

Considered unsustainable

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Yet, despite

� unprecedented resources expended - single biggest expenditure

of each province at near 1/2 of total program spending

� more MDs/population working in Canada than ever before (1/439)…

Canadian Institute for Health Information , Aug 2016

� Close to 1 in 5 Canadians unable to find a family doctor

� Longer waiting lists to see health providers

� Difficulty with access to care in many regions

� Extended waits for some investigations and for surgery

� Prolonged waits in emergency departments

• Bailey T. Waiting for a family doctor Can Fam Phys 2007;

• Canadian views on health care quality Results from the 2013 Commonwealth Fund International Health Policy Survey of the General Public.

http://healthcouncilcanada.ca/content_lm.php?mnu=2&mnu1=48&mnu2=30&mnu3=56

• Canada ranked last among OECD countries in health care wait times. http://www.ctvnews.ca/health/canada-ranked-last-among-oecd-countries-in-health-care-wait-

times-1.1647061

• Health Care in Canada, 2012. https://secure.cihi.ca/free_products/HCIC2012-FullReport-ENweb.pdf

� e.g. President of Canadian Medical Association 2011

Dr. Jeff Turnbull:

“Moral imperative to fix the Healthcare system

…. the time for action is now!”

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� Round tables, commissions, task forces, advisory panels, reports,

Romanow Commission, Mazankoski Report, Building on Values: the Future of Health Care in Canada,

Advisory Panel on Healthcare Innovation, etc, etc,

� Attempts by federal and provincial ministers to fix health care

e.g. Paul Martin “fix for a generation”

Yet, the problem with costs and availability of

services continues to escalate…

One of the main factors contributing to the

escalating problem has not been

adequately discussed & addressed…

Consider:

Horton R.

The neglected epidemic of chronic disease.

Lancet 2005: DOI: 10.1016/S0140-6736(05)67454-5.

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>80% of health care dealing with chronic illness

“The burden of preventable death and disease has

been growing, reducing the quality of life, increasing

wait times for health care, and challenging the

sustainability of the health care system.”

Treasury Board of Canada Secretariat. Departmental Performance Report 2005-2006. Public Health Agency of Canada. Section II – Analysis By Strategic Outcome And Key Program. 2006.

� Chronic diseases accounts for 86% of health care costs

� ½ all American adults have at least one chronic condition; almost 1/3

Americans has multiple chronic conditions

� 75% of the 2 Trillion dollars spent annually on healthcare goes to treating

chronic disease – most of which is preventable

• Centers for Disease Control and Prevention. Saving Lives, Protecting People. http//www.cdc.gov/chronicdisease/• US Department of Health & Human Services. Prevention makes common cents. https://aspe.hhs.gov/pdf-

report/prevention-makes-common-cents• http://www.fightchronicdisease.org/sites/default/files/docs/GrowingCrisisof ChronicDiseaseintheUSfactssheet 81009.pdf

"The number of people affected by Alzheimer's and

dementia is growing at an epidemic pace, and the

skyrocketing financial and personal costs will devastate

the world's economies and healthcare systems.“

William Thies, Ph.D.,

Chief Medical & Scientific Officer

Alzheimer's Association.

Med literature: Pritchard C, Rosenorn-Lanng E. Neurological deaths of American

adults (55-74) and the over 75's by sex compared with 20 Western countries 1989-

2010: Cause for concern. Surg Neurol Int. 2015;6:123

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“Health and social welfare systems are unprepared

for the rapid growth in demands that will arise

from these epidemics.”

Perrin JM, Bloom SR, Gortmaker SL JAMA 2007;297:2755-2759.

The increase in childhood chronic conditions in the United States.

� Weintraub Karen, The prevalence puzzle: Autism counts . Nature 479, 22-24 (2011) | doi:10.1038/479022a

� Hertz-Picciotto I, Delwiche L. The Rise in Autism and the Role of Age at Diagnosis. Epidemiology. 2009;20(1):84-91.

Better diagnosis?

Expanded criteria?

More seeking help?

.

Autism

� When I went to med school: 5% of Canadians will experience a

mental illness.

� An estimated 26.2 percent of Americans ages 18 and older — about

one in four adults — suffer from a diagnosable mental disorder in a

given year.

� A leading cause of disability in the U.S. and Canada.

• Kessler RC, Chiu WT, Demler O, Walters EE. Prevalence, severity, and comorbidity of twelve-month DSM-IV disorders in the National Comorbidity Survey

Replication (NCS-R). Archives of General Psychiatry, 2005 Jun;62(6):617-27.• The World Health Organization. The global burden of disease: 2004 update, Table A2: Burden of disease in DALYs by cause, sex and income group in WHO

regions, estimates for 2004. Geneva, Switzerland: WHO, 2008.

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Canada:

� Half of pediatric hospital beds filled to treat mental health problems

� Child and youth emergency visits for mental health issues increased 45%

(2007 to 2014)

USA:

� Visits for American youth with bipolar disorder increased >40 fold

(1994-2003)

Canadian Broadcasting Corporation. The Current. Half of all hospital beds in Canada for kids and youth filled to treat mental health. Thurs March 3rd 2016

Moreno C et al. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032-9.

In 1893 – Sir William Osler: Principles and Practices of

Medicine

� Diabetes: about 1:50,000 Americans

Now about 1 in 10 Americans

� Anticipate 50% increase in rates of cancer

over the next 15 years

� Significant increase in cancer in the young

as well as mature individuals

Marked Rise: U.S. Lifetime Cancer Rates:

2010 – Women: 1 in 3

Men: 1 in 2

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� Pediatric cancer up 40% in 16 years (1998-2014)

� The rise is most apparent in teenagers and young

adults aged between 15 and 24

Children with Cancer UK. Fourth international scientific conference. London, UK. Sept 5-7, 2016. http://childhoodcancer2016.org.uk/

� Increasing number of people living with chronic pain

� Waiting lists often >1 year for consultation at pain clinics

� 70 Million Americans live with chronic pain

� Escalating problem with adolescents living with chronic pain

Olorunto WA, Galandruk S. Managing the spectrum of surgical pain: acute management of the chronic pain patient. J Am Coll Surg 2006;202:160-75.Canadian Pain Society, Canadian Pain Coalition; Canadian Pain Foundation

Hundreds of thousands of people in some provinces with

unexplained environmental illnesses

� Sensitive to chemicals; Intolerant of many foods

� Chronic fatigue & multimorbidity

� Many become disabled

� Prevalence increasing quickly throughout the globe

Pall ML: Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms Chapter XX In 'General and Applied Toxicology', 3rd Edition.

Ballantyne B, Marrs TC, and Syversen T (Eds) . John Wiley & Sons, London. (2009)

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� What’s causing all this chronic physical and mental illness?

� Are environmental factors impacting human health?

….. What causes chronic illness?

1. Assess the Patient

2. Assign ‘Diagnosis’

3. Treat with Medicine or Surgery

4. Many spend the rest of their life coping with chronic illness

Common Algorithm for Clinical Management of Chronic Illness

Osteoporosis

Assessment Diagnosis Treatment

Bipolar Illness

Assessment Diagnosis Treatment

Rheumatoid Arthritis

Assessment Diagnosis Treatment

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Etiology often not explored

If there was a correctable causation, one would explore

& treat the cause to resolve the problem?

Fundamental Assumption…

The general algorithm of

Assessment Diagnosis Treatment

� Often presumes cause of chronic diagnosis is not readily explainable:

assumed genetic & non-correctable

Treat with Drugs

and Surgery

Is the genetic predestination paradigm consistent with recent science?

Genome

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Examples:

� Neurological Disease: e.g. Parkinson’s (Twin Study) - 49 pairs of identical

twins - one of the pair developed Parkinson’s and the other twin did not.

� Autoimmune Diseases: Growing number of genome studies support the role

of non-genetic factors leading to autoimmunity

Goldman SM, et al. Solvent exposures and Parkinson's disease. Ann Neurol. 2011 Nov 14.

Selmi C et al Heritability versus the role of the environment in autoimmunity. J Autoimmun. 2012;39(4):249-52.

� Why do so many have chronic

health afflictions that no one in

their ancestry has?

� Escalating rates of disease – our genes are

not changing.

� Does >3000% increase in ASD represent

3000% increased incidence of new genetic

mutations?

� No evidence of genomic issue in

overwhelming majority of ASD children

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1. Socioeconomic: Thyroid cancer incidence in Canada

is increased in high SEC groups

2. Nationality: Multiple sclerosis afflicts Canadians at a

rate that outpaces anyplace else in the world

3. Location of Residence: Thyroid cancer in Canada is

highest in Metro Toronto (controlled for SEC factors)

Genetics: Demographics

Corsten MJ, et al. Incidence of differentiated thyroid cancer in Canada by City of residence. J Otolaryngol Head Neck Surg. 2015;44:36.

� 2011: Somali Minnesota children 1:28 have ASD

� Immigrants from Japan

Genetics: Migration

There must be other factors along with genetics

that are contributing to health & illness!

What might they be?

Genome

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“Virtually all human diseases result from

the interaction of genetic susceptibility

and modifiable environmental factors.”

Office of Genomics and Disease Prevention: Centers for Disease Control and Prevention. Department of Health and Human Services. Gene-Environment Interaction Fact Sheet. 2000.

Recent Science: Paradigm shift

Genome Environment(modifiable)(fixed)

As a result of this shift in understanding…

� Many universities - primarily in Schools of Public Health e.g. Berkeley, Yale, University of

California, University of Alberta, etc.

� Objective: Assess the public health risks associated with biological, chemical and

physical hazards in natural and built environments (UA, School of Public Health)

Clinical Questions:

i) What is the link between Environmental health sciences & individual chronic illness?

ii) What are the practical implications for clinical practice?

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� 70-90% of chronic disease is primarily related to

environmental determinants

� Current reality: most clinical trainees have not been educated

in details of environmental determinants of health

• Rappaport SM, Smith MT. Epidemiology. Environment and disease risks. Science. 2010;330(6003):460-1.

• Wu S, Powers S, Zhu W, Hannun YA. Substantial contribution of extrinsic risk factors to cancer development. Nature. 2015.

• Our genes are not our destiny: incorporating molecular medicine into clinical practice. J Eval Clin Pract. 2008;14(1):94-102

Health care system – serious challenges

Epidemic of chronic disease

Environmental factors

Health providers need training in environmental health sciences to

clinically assess and manage environmental determinants of health

Genome Environment(modifiable)(fixed)

What are the clinically significant environmental factors?

CDC: “Virtually all human diseases result

from the interaction of genetic susceptibility and

modifiable environmental factors.”

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Environment

(modifiable)

Genome

(fixed)

Sufficiency

Toxic Exposurese.g. chemicals.

pathogens, radiation, etc

Genuis SJ. What's out there making us sick? J Environ Public Health. 2012;605137.

Any functional system

Chronic illness is primarily caused by factors in 2 categories:

� Deficiency of what the body requires

� Exposure and/or accrual of toxic factors

Genome Environment(modifiable)(fixed)

Secure

Sufficiency

Address

Toxicity

Environmental Medicine

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� Auto-immune

� Hormonal (Endocrine)

� Chemical Imbalance

� Vascular

� Degenerative

� Neoplastic

� Inflammatory

� Metabolic

� Etc.

Mechanisms

DiseaseMechanism or

Pathophysiology

Pathway to any Illness…

Clinical Signs &

SymptomsUnderlying

root origin

Cause Process (Pathogenesis) Effect (manifestation)

What it does to the body

Alteration of biochemistry

& physiology

i) Toxicants as cause…

Etiology

• Carcinogenic

• Neurotoxic

• Immunotoxic

• Hepatotoxic

• Nephrotoxic

• Cardiotoxic

• Developmental toxicity

• etc. etc

Toxic

Exposures

The chemical erosion of human health: Adverse environmental exposure and in-utero pollution – determinants of congenital disorders and

chronic disease. Journal of Perinatal Medicine 2006; 34:185-95.

Genuis SJ, Kyrillos E. The chemical disruption of human metabolism. 2016.

Many

Pathophysiological

Changes

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CELLULAR TOXICITY PATHOPHYSIOLOGY

Damage to Cell Structures -e.g. DNA, mitochondria* Endocrine Disruption *

Oxidative Stress* Inflammation

Receptor and Transporter Dysregulation Immune Dysregulation *

Epigenetic Change Pathway Impairment

Cellular Detoxification Impairment Biome Alteration

Dysregulation of Signalling ANS Dysregulation

Plaque Formation Neurotransmission Dysfunction *

Displacement Nutritional Compromise

Other Mechanisms of Cellular Toxicity Other Pathophysiological Mechanisms

Genuis SJ, Kyrillos E. The Chemical Disruption of Human metabolism. 2016.

Hormonal

Dysregulation

� Elevated or insufficient

level of hormones

� Resistance to hormonal

messages

� etc

Endocrinopathy

• Addison’s

• Thyroid

• Diabetes

• PCOS

• Cushings

• etc

• etc

Why?

Pathophysiology DiseaseEtiology

Hormonal

BPA , other plasticizers

DDT & PCBs, etc

PBDEs, Triclosan, etc

Phthalates, etc

PCBs,etc

Fungicide (Mancozeb) etc

Metals (Pb, Hg, Cd, etc)

Organochlorines, etc

etc…

Binds thyroid hormone receptors

Bind TSH receptor

Induction of thyroid autoantibodies

Blocks Iodide uptake

Binds thyroid transport protein

Impairs thyroid hormone production

Inhibition of Deodinases

Direct Thyrotoxicity

• Brent GA. Environmental Exposures and Autoimmune Thyroid Disease.Thyroid. 2010 Jul; 20(7): 755–761.

• Takser L et al.. Thyroid hormones in pregnancy in relation to environmental exposure to organochlorine compounds and mercury. Env Health Perspect. 2005;113(8):1039-45

• Crofton KM. Thyroid disrupting chemicals: mechanisms and mixtures. Int J Androl. 2008 Apr;31(2):209-23

• Shen O, Comparison of in vitro hormone activities of selected phthalates using reporter gene assays. Toxicol Lett. 2009 Dec 1;191(1):9-14.

• etc. etc.

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Autoimmune

� Autoantibodies

� Cytokine storm

� Etc.

A/I Disease

� Crohn’s

� Ulcerative colitis

� Sjrogen’s

� Iritis

� Multiple Sclerosis

� Hashimoto’s

� etc

Why?

Pathophysiology DiseaseEtiology

Autoimmune

e.g. 9/11 responders, Gulf war vets, Bhopal pesticide,…

Chemical imbalance

� Neurotransmitter dysreglation

� Serotonin deficiency

� GABA dysregulation

� Glutamate disturbance

� Dopamine disorder

� Norepinephrine disorder

� Melatonin disruption

� etc.

Mental Health

Problem

� Depression

� Anxiety

� Autism

� Thought disorder

� Panic

� Obsessive

� Dementia

� etc

Why?

Pathophysiology DiseaseEtiology

Chemical imbalance

EnvironmentGenome

Deficiencies

Toxic

Exposures

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Adverse

Clinical

Outcomes

Deficiencies

The chemical erosion of human health: Adverse environmental exposure and in-utero pollution – determinants of congenital disorders and

chronic disease. Journal of Perinatal Medicine 2006; 34:185-95.

Genuis SJ, Kyrillos E. The chemical disruption of human metabolism. 2016.

Many

Metabolic

Alterations

� Zinc levels (an essential nutrient required as a cofactor for more than 300 enzymes)

� Zinc deficient animals – expression of pathological genes for esophageal cancer

� Restoration of zinc levels – turning off of pathological genes – regression of disease changes

Fong LY, et al. Dietary zinc modulation of COX-2 expression and lingual and esophageal carcinogenesis in rats. J Natl Cancer Inst 2005; 97:40-50.

Fong LY, et al.. Esophageal cancer prevention in zinc-deficient rats: rapid induction of apoptosis by replenishing zinc. J Natl Cancer Inst 2001; 93:1525-33.

Recent: Vitamin D has 2776 “binding sites” on the human genome

Involved in regulation of myriad biochemical process throughout life

Most of the population in northern climates are considered deficient

Level associated with optimal health: 100–150 nmol/L

Average 25(OH)D3 levels: 60 -70 nmol/L

• K. Amrein et al., “Evidence for a U-shaped relationship between prehospital vitamin D status and mortality: a cohort study,” J Clin Endo Met ;99: 1461–1469, 2014.

• S. V. Ramagopalan, et al., “A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution,” Genome Research,

vol. 20, no. 10, pp. 1352–1360, 2010

• Schwalfenberg G: Not enough vitamin D: health consequences for Canadians. Can Fam Physician 2007, 53:841-854.(Holick and Chen 2008)

• Holick MF, Chen TC: Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 2008, 87:1080S-1086S.

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Lancet publication - VTD improvement:

� Prospective study of colon cancer risk based on levels of 25(OH)D - >25,000 participants followed

� 75-80% reduction in risk for colon cancer for higher levels vs. low levels

Garland, C.F.; Comstock, G.W.; Garland, F.C.; Helsing, K.J.; Shaw, E.K.; Gorham, E.D. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 1989, 2, 1176-1178.

Environmental determinants

Deficiency & toxicity

Causative with regards clinical illness

Genome Environment(modifiable)(fixed)

Secure

Sufficiency

Address

Toxicity

Environmental Medicine

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1. Assess the Patient

2. Assign ‘Diagnosis’

3. Explore the Cause(s) of the ‘Diagnosis’

4. Intervene Accordingly

A. Extensive History (Referral)

B. Exam

C. Laboratory Evaluation

� Deficiency (biochemical analysis)

� Toxicity (toxicology testing)

� Metabolic function (metabolomics - chemical fingerprints of cellular processes)

D. Environmental Assessment

E. Interventions

� to address deficiencies and toxicities

� to mitigate metabolic dysfunction when possible

DiseaseMechanism or

Pathophysiology

Environmental Medicine - Clinical Approach

Identify &

Address

Causation

Intervene to

mitigate harm

when possible

Case reports…

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� Insulin dependent diabetic

� Chronic severe headaches and neurological issues: numbness in trunk and limbs

� Recurrent dermatologic issues

� etc, etc…Refractory to various treatments in the past

Toxicological testing: v. high PCB content –Arachlor 1254 (mixture of PCB congeners)

Rx with non-absorbable fat Rx- Lipophilic “sink” x 2 years.

Result:

� PCBs dropped markedly (3200 mg/kg to 56 mg/kg)

� normoglycemic, off insulin

� Resolution of other symptoms - marked clinical improvement

Redgrave et al. (2005)Treatment with a dietary fat substitute decreased Arochlor 1254 contamination in an obese diabetic male. J Nutr Biochem ;16(6):383-4.

Jandacek RJ, et al. (2014) Reduction of the body burden of PCBs and DDE by dietary intervention in a randomized trial. J Nutr Biochem 25: 483-488.

� 62 year old with 33 year history of bipolar illness.

Recent development of progressive dementia.

� Memory, comprehension, communication and

reasoning - rapidly declining.

� “Irreversible, degenerative condition.”

� Recommendation: chronic care placement.

Genuis SJ, Kelln KL. Toxicant exposure and bioaccumulation: a common and potentially reversible

cause of cognitive dysfunction and dementia. Behav Neurol. 2015;2015:620143.

� Assessment: History of work with stained glass in confined

space – lead exposure

� Massive amounts of lead on challenge test; minimal levels on

blood testing

� Pb detoxification: over 9 months, astonishing recovery in

mentation & mood

� Good sense of humor. “Great to have the man I married back in

my life.”

Other case reports available on Researchgate

Genuis SJ, Kelln KL. Toxicant exposure and bioaccumulation: a common and potentially reversible cause of

cognitive dysfunction and dementia. Behav Neurol. 2015;2015:620143

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A. Knowledge translation esp. re toxic agents

� Process to translate research to clinical practice – many questions

B. Challenges within clinical practice

KT & toxic agents… mtg

� Father of Toxicology: Paracelsus

� (On the Miners' Sickness and Other Diseases of Miners )

� Mad Hatter (Occupational Hg exposure)

� Beethoven, Van Gogh (Pb exposure)

� etc

� Bioaccumulation

� Accrual of various toxic chemicals in cigarettes recognized as a determinant of

many illnesses

*Now, a plethora of other low-dose chemical exposures

that people are routinely exposed to.

(some are at least as toxic as smoking)

Doll R, Hill AB. (1954). The mortality of doctors in relation to their smoking habits. BMJ 328.

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• Inherent physiology occurring as a result of biochemical

reactions involving ppb & ppt

• Endogenous Free Estradiol Adult Women (Serum)

• 0.6-7.1 pg/ml (mass/volume) = 0.0006-0.0071 ppb (mass fraction)

• Endogenous Free Testosterone Adult Men aged 20-25 (Serum)

• 5.25-20.7 ng/dl (mass/volume) = 0.0525-0.207 ppb (mass fraction)

Welshons WV, et al. (2003) Large effects from small exposures. Environ Health Perspect 111,994–1006.

Mayo Clinic Laboratories. Testosterone, Total, Bioavailable, and Free, Serum. available and accessed Aug 14,2016 at [http://www.mayomedicallaboratories.com/test-

catalog/Clinical+and+Interpretive/83686]. 2016.

Dynacare-Gamma Laboratory Partnership. Estradiol. Accessed August 14, 2016 at [https://www.dynacare.ca/specialpages/secondarynav/find-a-

test/nat/estradiol.aspx?sr=ont&st=estradiol&]. 2016.

Dermal exposure (e.g. BPA cash receipts)

Ingestion exposure

Inhalation exposure

Gao X et al. Impact of bisphenol A on the cardiovascular system - epidemiological and experimental evidence and molecular mechanisms. Int. J Envron Res Public Health. 2014 Aug 15;11(8):8399-413.

� 3.7 million deaths

attributable to ambient air

pollution

� 4.3 million deaths

attributable to indoor

air pollution

World Health Organization. Public health, environmental and social determinants of health (PHE) http://www.who.int/phe/health_topics/outdoorair/databases/en/

7-8 million deaths/year as a result of contaminants within the air

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Centres for Disease Control – 2015

� Most American adults and children have accumulated numerous potentially toxic chemicals

� Health Canada

� Underestimates body burden e.g. Pb accrual in tissues

Centres for Disease Control. Fourth national report on human exposure to environmental chemicals. Updated tables 2015.

http://www.cdc.gov/biomonitoring/pdf/FourthReport_UpdatedTables_Feb2015.pdf . 2015.

Environmental Working Group. Body burden - the pollution in newborns A benchmark investigation of industrial chemicals, pollutants and pesticides in umbilical cord blood. (Executive Summary) July 14, 2005. [Accessed Sept 16, 2005]

http//ewg.org/reports/bodyburden2/execsumm.php .

American Red Cross collected Cord Blood Samples:

� Most compounds not tested

� Testing is brief exposure – real life may include

persistent ongoing exposure of accrued toxicants

� Only looking at short term outcomes

� Detoxification mechanisms different in rats

Rat Genome Sequencing Project C. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature. 2004; 428: 493–521.

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Can’t do RCTs by exposing people to potentially

harmful factors – must rely on observational evidence

No RCTs gestational alcohol use or seatbelts, etc

� Objectives: To determine whether parachutes are effective in

preventing major trauma related to gravitational challenge.

� Design: Systematic review of randomised controlled trials.

� Main outcome measure: Death or major trauma

� Results: We were unable to identify any randomised controlled

trials of parachute intervention

Parachute use to prevent death and major trauma related to gravitational challenge:

systematic review of randomised controlled trials. BMJ 2003; 327:7429.1459

� Advocates of evidence based medicine have criticised the adoption of

interventions evaluated by using observational data.

� As with many interventions intended to prevent ill health, the effectiveness of

parachutes has not been subjected to rigorous evaluation by using randomised

controlled trials

� We think that everyone might benefit if the most radical protagonists of evidence

based medicine organised and participated in a double blind, randomised,

placebo controlled, crossover trial of the parachute.

Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003; 327:7429.1459

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Extensive number of papers in the scientific literature demonstrating a link between low level toxicant exposures and all kinds of conditions including cancer, mental health problems, reproductive difficulties, etc

Environmental Health Perspectives

Environmental Research

Toxicological Sciences

J. Environmental and Public Health

Environmental Science and Technology

Research Journal of Environmental Toxicology

Environmental Science and Policy

etc.

Pediatric Academic Societies - Annual Meeting:

“Low level exposure to environmental toxicity may be impacting the

functioning of the current generation”

World Health Organization:

“Acute and chronic, high and low-level exposures to chemicals in the

environments of children may cause functional and organic damage.”

International Federation of Gynecology and Obstetrics 2015

“Exposure to toxic environmental chemicals during pregnancy and

breastfeeding is ubiquitous and is a threat to healthy human reproduction.”

• Journal of Perinatal Medicine:Volume 34(3)May 2006. 185–195

• World Health O. Children's Health and the Environment. WHO Training Package for the Health Sector. [www.who.int/ceh accessed Jul 8, 2009].• Di Renzo GC et al. International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals. Int J Gynaecol

Obstet. 2015.

• Rossignol D et al. Environmental toxicants and autism spectrum disorders: A systematic review. 2014. Translational Psychiatry.

• CDC figures. http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6103a1.htm?s_cid=ss6103a1_w• Prevalence of Autism Spectrum Disorders --- Autism and Developmental Disabilities Monitoring Network, United States, 2006. MMWR 2009; 58(SS10);:1-20.

• Geier MR, Geier DA. Thimerosal in childhood vaccines, neurodevelopment disorders, and heart disease in the United States. J Am Phys Surg. 2003;8(1):6-11.• Production of Synthetic Organic Chemicals.The Paradox of Progress: Environmental Disruption of Metabolism and the Diabetes Epidemic. http://diabetes.diabetesjournals.org/content/60/7/1838.full#ref-72.

Updated from: Neel BA & Sargis RM. Diabetes 2011;60:1838-48.

Considerable evidence linking many persistent pollutants with ASD

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• Breast Cancer.Canadian Cancer Society/National Cancer Institute of Canada (2006, April) Table 8.1

http://www.cancer.ca/~/media/cancer.ca/CW/cancer%20information/cancer%20101/Canadian%20cancer%20statistics/Canadian-Cancer-Statistics-2006-EN.pdf• Production of Synthetic Organic Chemicals.The Paradox of Progress: Environmental Disruption of Metabolism and the Diabetes Epidemic. http://diabetes.diabetesjournals.org/content/60/7/1838.full#ref-72.

Updated from: Neel BA & Sargis RM. Diabetes 2011;60:1838-48.

Some evidence linking xenoestrogenic pollutants as causative determinants in breast cancer

• Derouiche et al. 2013 Dec;2(1):54. Springerplus. Bisphenol A stimulates human prostate cancer cell migration via remodelling of calcium signalling..

• Prostate Cancer. Canadian Cancer Society/National Cancer Institute of Canada (2006, April) Table 7.1http://www.cancer.ca/~/media/cancer.ca/CW/cancer%20information/cancer%20101/Canadian%20cancer%20statistics/Canadian-Cancer-Statistics-2006-EN.pdf

• Production of Synthetic Organic Chemicals.The Paradox of Progress: Environmental Disruption of Metabolism and the Diabetes Epidemic. http://diabetes.diabetesjournals.org/content/60/7/1838.full#ref-72. Updated from: Neel BA & Sargis RM. Diabetes 2011;60:1838-48.

- Some evidence linking prostate cancer to xenoestrogenic toxicants

Infertility

Bushnik et al. Estimating the prevalence of infertility in Canada. Hum Reprod. 2012 Mar;27(3):738-46.

Production of Synthetic Organic Chemicals.The Paradox of Progress: Environmental Disruption of Metabolism and the Diabetes Epidemic.

http://diabetes.diabetesjournals.org/content/60/7/1838.full#ref-72. Updated from: Neel BA

Indirect evidence that endocrine disrupting compounds may be determinants of many infertility states – disruption of sperm production & ovulation

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1. Not covered by health care in Canada

� Tox testing expensive – comparatively miniscule to hospitalization

� Savings – back to work, not in hospital, no longer disabled…

2. Requires patient perseverance & compliance

� Not fast food medicine; Takes time to get stuff out

3. Lack of physicians trained in EM

� 70-90% illness related to environmental factors

� Lack of integration: basic EM education needed in med school & residencies.

Often: Laundry list of ongoing and seemingly unrelated complaints

Symptoms often include (direct questioning)

� Ongoing fatigue

� MSK issues myalgias, joint pain, etc

� CNS issues – may include headache, brain fog, memory issues, etc

� Psych issues - mood changes, inexplicable anger, anxiety, panic, etc

� GI issues – bloating, pain, constipation, etc

� Environmental Sensitivities – foods, chemical, pollens, etc

� etc

� Repeated visits to their primary practitioners

� High rates of attendance in emergency departments

� Poor long term health outcomes in most - often become disabled

� Health care costs are enormous

� Barnett K, et al. (2012) Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 380: 37-43.

� Lehnert et al. (2012) [Effects of multimorbidity on health care utilization and costs]. Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 55: 685-692.� Smith SM, et al. (2012) Interventions for improving outcomes in patients with multimorbidity in primary care and community settings. Cochrane database of systematic reviews 4: CD006560.

� Jakovljevic et al. (2010) Comorbidity, multimorbidity and personalized psychosomatic medicine: epigenetics rolling on the horizon. Psychiatria Danubina 22: 184-189. � Genuis SJ (2014) Pandemic of idiopathic multimorbidity. Canadian family physician Medecin de famille canadien 60: 511-514, e290-513.

� Thomason C (2013) Changes needed to cope with multimorbidity. Nursing times 109: 32.

What appears to be the source cause?

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Primary Toxic Insult(s):

+ Adverse persistent chemicals

e.g. flame retardants, organic solvents, PCBs, organochlorine pesticides, etc

+ Chronic infectione.g. mold exposure with biotoxins, lyme, etc

+ Some dental materials

+ etc.______________________________________________________________________________________________________ ______________________________________________________________________________________________________ ______________________________________________________________________________________________________ _______________________________________

Total Body Burden = Total Load

� Immune – self vs. non-self

� When the burden exceeds a threshold……….stage #2

Toxicant Induced Hypersensitivity

I. Heavy toxicant burden

II. Immune System Dysregulation (Hypersensitivity)

• *Miller CS. Are we on the threshold of a new theory of disease? Toxicant-induced loss of tolerance and its relationship to addiction. Toxicol Ind Health 1999;15:284-94.

• Dantoft T, et al. An elevated pro-inflammatory cytokine profile in un-exposed individuals with multiple chemical sensitivity. Psychoneruoenodcrinology 2014 Feb;40:140-50.

• Genuis SJ. Chemical Sensitivity: Pathophysiology or Pathopsychology? . Clinical therapeutics 2013; 35 572-7.

‘TILT’: Toxicant Induced loss of tolerance*

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II. Hypersensitive immune system

III. Trigger (Incitant)

e.g. food, chemical, inhalant, etc.

Abnormal Immune Response with

Assorted Symptoms

Triggering of Myriad Clinical Symptoms

potential IgE, IgG, IgA, pro-inflammatory cytokine storm, etc

various pro-inflammatory cytokines can affect genetic expression,

cell regulation (cell signalling molecules), hormonal impact, etc

Varied Clinical Symptoms

of environmental illnesses

Can affect one or more organ systems

• Dantoft T, et al. An elevated pro-inflammatory cytokine profile in un-exposed individuals with multiple chemical sensitivity. Psychoneruoenodcrinology 2014 Feb;40:140-50.

• Genuis SJ. Chemical Sensitivity: Pathophysiology or Pathopsychology? . Clinical therapeutics 2013; 35 572-7.

Toxicant Burden

Hyper-Reactive Immune System

Triggers Evoke Symptoms

• Genuis SJ. Sensitivity-related illness: the escalating pandemic of allergy, food intolerance and chemical sensitivity. The Science of the Total Environment 2010;408:6047-61.

• Miller CS. Are we on the threshold of a new theory of disease? Toxicant-induced loss of tolerance and its relationship to addiction and abdiction. Toxicol Ind Health 1999;15:284-94.

• Ashford N, Miller C. Chemical Exposures: Low Levels and High Stakes (2nd ed.) New York: John Wiley and Sons. 1998.

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SRI can be induced in animals by exposure to

toxic chemical insults

Rogers WR, Miller CS, Bunegin L (1999) A rat model of neurobehavioral sensitization to toluene. Toxicol Ind Health 15: 356-369.

Overstreet DH et al. (1996) Potential animal model of multiple chemical sensitivity with cholinergic supersensitivity. Toxicology 111: 119-134.

Sorg BA, Hochstatter T (1999) Behavioral sensitization after repeated formaldehyde exposure in rats. Toxicol Ind Health 15: 346-355

1) Secure safe place away from triggers

2) Educate on avoidance

3) Identify & remove toxicant burden(discuss ‘detox’, ‘cleanse’)

4) No longer metabolic disruption

5) Clinical improvement or resolution

• Genuis SJ. Sensitivity Related illness. The Science of the Total Environment 2010;408:6047-61/

� Healthcare system in seriously challenged

� Pandemic of chronic illness: enormous personal suffering

� Most being caused by environmental factors

� Clinically, much can be done to assist individuals and society

� Environmental Healthcare training needs to be adopted soon

Published papers on this and EM in general (Indexed at PubMed) &

(Available at Researchgate)

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Stephen J. GenuisMD FRCSC DABOG DABEM FAAEM

Clinical Professor

University of Alberta