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EnvironmentalFactorsGeneticsMolecularEpidemiology-Fall 2004 _08-34_


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									     Environmental Factors,
      Genetic & Molecular                                        Part I
          Epidemiology                                Overview of toxic exposures
                                                        in the environment and
       Lynn T Frame, Ph.D., DABT
     Department of Pharmacology and

Common Environmental Toxicants                             Occupational Hazards
• Heavy metals-cadmium, lead, uranium, mercury.      • Examples:
• Persistent organic pollutants-dioxins, PCBs,         – Noise
  DDT, DDE, toxaphene.
                                                       – UV light
• Solvents-benzene, hexane, methanol.
• Air pollutants- ozone, photochemical smog,           – Extremes of heat and cold
  oxides of nitrogen and sulfur, particulates.         – Chemical exposure (both acute and chronic)
• Radiation-ionizing (radon, fallout, cosmic rays,     – Radiation
  etc.) and non-ionizing (radio waves,                 – Infectious agents- HepA, HepB, AIDS, etc.
  microwaves, cell phones, electromagnetic
  radiation from high-voltage electrical wires.
Regulation is different for environmental and
           occupational hazards                            Dose vs. Exposure
• Hazards found in the environment or           • Dose is a quantifiable exposure to a substance
                                                  resulting in a measurable effect. Increasing
  encountered at work.                            dose results in increasing effect after a threshold
• Environmental toxicants regulated on the        dose has been exceeded and until saturation of
  assumption of continuous exposure: 70 kg        the system occurs.
  adult exposed continuously for 70 years at    • A typical dose-response curve is thus sigmoidal
                                                  in shape. However, other shapes result when
  highest concentration found.                    multiple mechanisms of action occur.
• Occupational hazards regulated on 8 hour      • It is difficult to measure dose in environmental or
  day, 40 hour work week.                         occupational studies; thus, the term exposure is

       Exposure to Mixtures                                 Timing of Effects
• Exposure to a single compound is the          • The time period between exposure and
  exception rather than the rule. In fact,        appearance of effects is called latency.
  most exposures are complex,                   • However, this does not mean damage did
  uncharacterized mixtures.                       not occur at the time of exposure.
• Individual components may affect the          • Acutely toxic agents often act by
  toxicity of other compounds. Interactions       damaging lipid bilayers, specific proteins,
                                                  or interfering with calcium levels.
  are usually classified as agonistic ,
  antagonistic, synergistic or potentiating.    • Agents with a long latency are usually
                                                  mutagens which damage DNA.
Dose-response vs. Exposure-effect                        Exposure Assessment
• Dose-response relationships are used in        • Exposure can be determined directly, indirectly,
  pharmacology and experimental toxicology         or inferred by environmental measurements.
  because the dose is known and response         • Direct measurement can be blood levels, tissue
  can be measured quantitatively at the            levels, or breath levels.
  target site.                                   • Indirect measurement may be concentrations in
                                                   urine, feces or on the skin.
• In environmental toxicology and
                                                 • Environmental measurements include soil,
  epidemiology, exposure and effect must           water, food or air concentrations. However,
  often be inferred or qualitatively               these concentrations may not reflect exposure
  determined.                                      since bioavailability is frequently unknown.

        Descriptive Surveys                          Descriptive Surveys cont’d
Useful for multiple reasons:                     5. Diagnose employees with mild curable disorders
  1. Survey regularly workers exposed to known   6. Diagnose chronic disease which require regular
     occupational hazards.                          control
  2. Examine workers coming into contact with    7. Identify workers who are not suitable for certain
     new health hazards.                            jobs (i.e. those with allergies, chronic bronchitis,
  3. Close surveillance of employees with           back disorders).
     increased sensitivity to work-related
     disease.                                    8. Keep those employees with unhealthy life-styles
                                                    under close scrutiny (heavy smokers and drinkers,
  4. Identify workers with exceptional risk to
     other disease for preventative action.         obese) in order to help them cope with their
     Adverse Health Outcomes                                    Internal Validity is Goal
• Death                                                  • Selection Bias-arises when the exposure or
• Increased Cancer Rates (leukemia, lung,                  presence/absence of disease systematically
                                                           influences whether subjects are recruited into
• Cataracts and Blindness
• Chronic Obstructive Pulmonary Disease (byssinosis,
                                                           the study.
  asbestosis, silicosis, baggosis)                       • Information Bias-occurs when there is
• Asthma (Bakers’ asthma, Carpenter and Loggers,           asymmetry in the quality of the data on the study
  Carpet Layers)                                           and reference groups. Masks true differences.
• Contact Dermatitis
• Multiple Chemical Sensitivity Disorder                 • Comparison Bias-arises if the control group is
• Sterility, birth defects and other reproductive          not the study group without exposure to the
  abnormalities                                            agent of concern.
• Neurodegenerative diseases-neuropathies, Parkinson’s

        Healthy Worker Effect                              Remember Sir Percival Pott?
• Reduces the validity of exposure data                  • First epidemiological study in occupational
  because employed populations,                            medicine, published in 1775.
  particularly with health surveillance plans,
  have lower mortality than the general                  • Observed a remarkably high incidence of
  population.                                              scrotal cancer in chimney sweeps.
• Moreover, individuals with chronic illness               Chimney sweeps often started as young
  are less likely to be employed.                          boys whose clothing became impregnated
• Stronger for non-cancer mortality than                   with soot, and rarely changed or washed.
  cancer mortality.                                      • Soot contains benzo[a]pyrene.
                   Cancer                               Chronic Nonspecific Respiratory
• Scrotal cancer-PAH exposure-chimney
  sweeps.                                             • Includes chronic bronchitis, emphysema and
• Bladder cancer-naphthylamine and                      asthma.
  benzidine dyes – dye workers.                       • Risk factors include smoking air pollution,
                                                        socioeconomic status, familial and genetic
• Benzene-leukemia-rubber and tire                      factors, atopy, bronchial reactivity, and
  workers.                                              occupational exposures.
• Problems-long latent period, exposure to            • Occupations with elevated incidence include
  mixtures, repeated studies of known                   miners, steel workers, foundry workers, pulp mill
  carcinogens, lack of mechanistic studies.             workers, bakers, organic chemicals,
                                                        pharmaceuticals, farmers and cotton workers.

         Endocrine Disruption                             Musculoskeletal Disorders
• Can act upon fetuses or adults to either cause      • Chronic lower back pain is a common
  developmental malformations, sterility, or            complaint among laborers and is a
  cancer.                                               symptom of degenerating spinal
• Diethylstilbestrol (DES), administered to prevent     structures.
  miscarriage, caused vaginal clear cell adenomas
  in daughter and granddaughters. It caused           • Exposure (history of poor lifting practices
  phallus, testes and prostate problems in sons.        vs. high risk jobs) is difficult to quantitate.
• DBCP and EDB caused testicular atrophy in           • Effects are also difficult to quantitate
      Coronary Heart Disease                                   Behavioral Responses
• Various chemical exposures have been linked to      • Mental stress can be caused by shift work, work
  increased risk of CHD in addition to age, gender,     overload, boredom, under-use of cognitive
  smoking , serum cholesterol and blood pressure.       abilities, discrepancies between expectations
                                                        and capabilities, and hostile worker-worker or
• These include carbon disulfide, organic nitrates,     worker-supervisor interactions.
  arsenic and organic solvents. Data are
                                                      • Additionally, noise, heat, and neurotoxic
  inconclusive for carbon monoxide, cadmium and         chemical exposure can also cause mental
  lead.                                                 stress.
• Heat, cold, and humidity are work factors that      • These can cause behavioral and psychosomatic
  influence cardiovascular mortality.                   symptoms.

   Behavioral and Psychosomatic                            Results of work-related mental
            Symptoms                                                   stress
• In Sweden:                                          •   Smoking
                                                      •   Alcohol abuse
• 33% of workers suffer from malaise, sleep           •   Overeating
  disorders, fatigue, dejection and anxiety.          •   Lack of physical exercise
• 1/7 are exhausted at the end of the                 •   Mental disorders
  workday.                                            •   Mass psychogenic disease
                                                      •   Gastrointestinal symptoms
• 50% of men and 33% of women suffer                  •   Cardiovascular symptoms
  from one or more breakdowns by the age              •   Neurotic symptoms
  of 60.                                              •   Frigidity and impotence
        Possible Mechanisms                                                 Interactions
• Neuroendocrine reactions- specifically              • Agonistic interactions occur when the
  perturbations of hypothalamic-pituitary-
  adrenomedullary/adrenocortical axies.                 effects are additive.
• Immune reactions                                    • Antagonistic interactions result when one
• Both explorative and cross-sectional studies          compound reduces the toxicity of another,
  have been used to study such disorders. Best
  studies have been longitudinal etiologic studies.     usually by competition at the target site.
• Influences of emotions so great that few studies    • Synergism results when two toxicants
  have produced constant results.
• Choice of a valid reference group particularly
                                                        acting together are much more toxic, for
  difficult.                                            example tobacco smoke and asbestos.

                                                                 Smoking and asbestos exposure
 Example: Smoking and Asbestos                                     and lung cancer mortality
                                                                   Source: http://whitelung.org/pubs/workexp/smoking.html

• It has been observed that asbestos                  Groups      Exposure           History of          Death              Mortality
                                                                  to                 Cigarette           Rate               Ratio
  workers who smoked cigarettes had a                             Asbestos           Smoking
  much higher incidence of lung cancer than           Control     No                 No                  11.3               1
  workers who did not smoke or smokers
  who did not work with asbestos.                     Asbestos    Yes                No                  58.4               5.17
                                                      Control     No                 Yes                 122.6              10.85

                                                      Asbestos    Yes                Yes                 601.6              53.24
      Smoking and Asbestos                       Other Types of Interactions
Why a synergistic effect?                   • In addition to environmental interactions, there are:
                                                – Gene-gene interactions
• Cigarette smoke contains polynuclear          – Gene-environment interaction
  aromatic hydrocarbons which are           • Genetic diseases always have environmental triggers
  bioactivated into mutagens, causing       • Underlying gene-environment interactions first elucidated
  initiation.                                 by studying very rare diseases associated with very high
• Asbestos fibers irritate the type I       • Trend has been toward understanding very common
  pneumocytes resulting in proliferation.     genes with small elevations in risk (ie. genetic
                                              polymorphisms in drug-metabolizing enzymes)
  Thus, we have initiation and promotion,
  the keys to cancer.

    Causes of Familial Aggregation                 Non-genetic reasons why
                                                    diseases run in families
• Genetic                                   • Chance
• Non-Genetic                               • Age
                                            • Family Size
                                            • Sharing of a bad environment- cigarettes, diet,
                                              water supply, radon in soil, air quality,
                                              pesticides, lead paints, occupation, poor
                                              sanitation or health care, infectious disease
                                            • Variables must be accounted for statistically, or
                                              acknowledged as possible confounders in any
                                                              Gene polymorphisms
                                                              responsible for differential
        Remember the Flow of Information                      risk in environmental

                                                              Specific environmental
                             • Phenotype: physical            interactions required for the
                               expression of genetic          expression of differential
                                                              Polymorphic genes
                                                              (enzymes, proteins) drive
                                                              the processes that
                                                              bioactivate pro-
                                                              carcinogens. They also
                                                              drive the processes that
                                                              metabolize, repair, and
                                                              perform surveillance.
                             • Genotype: blueprint            Genes also underlie
                                                              interindividual differences
                               for the phenotype              in behavior: these are
                                                              important in risks for
                                                              environmental disease

      Molecular Epidemiology in                                            Advantages of Molecular
    Occupational and Environmental                                        Epidemiological Approaches
              Research                                         • May be able to avoid recall or other
• Dividends for use of biomarkers of exposure and                subjective biases
  effect in epidemiological studies                            • Document pathological changes that
  – Improvements in the classification of exposures
  – More accurate definition of risk groups through the use
                                                                 characterize early stages of a disease
    of susceptibility markers                                  • May be able to deduce mechanisms of
  – Increased specificity in the classification of disease
  – Greater understanding of etiologic mechanisms for
    disease – ie the role of DME polymorphisms in risk for     • Biomarkers may provide a rationale for a
    chronic health problems associated with chemical
    exposure                                                     specific treatment
Non-Research Applications for Mechanistic
  Information obtained from Molecular              Care in Interpretation of Studies
        Epidemiological Studies
• Screening for genetic susceptibility (caution)    Correlation is not causation
• Early detection of disease                        Candidate genes may only be “close” to gene of
• Targeting of high-risk population subgroups         interest
  for interventions                                 Investigator must ask whether there is selection
• Tailored prevention approaches that                 bias, confounding, misclassification
  recognize underlying differences in host          Environmental triggers for disease must be
  susceptibility                                      identified and monitored for proper
• Development of new therapies and                    interpretation of findings
  treatments for disease

        Take-Home Message                                          Conclusions
                                                   • Risk of diseases are not random.
   • Statistical dependence between two            • Controllable factors related to lifestyle and
     or more events, characteristics, or             environment can be characterized in hypothesis-
     other variables.                                driven studies.
                                                   • Genetic and molecular epidemiologists of the
                                                     future will need to be trained in interdisciplinary
   • Association is not causation!

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