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,
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
• 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
• 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
• 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
responsible for differential
Remember the Flow of Information risk in environmental
• Phenotype: physical interactions required for the
expression of genetic expression of differential
(enzymes, proteins) drive
the processes that
carcinogens. They also
drive the processes that
metabolize, repair, and
• Genotype: blueprint Genes also underlie
for the phenotype in behavior: these are
important in risks for
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
• 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!