6. Epidemiological Toxicology

Question 1

What are the different methods used to identify a hazard?

Answer 1

1. Epidemiology
2. Toxicology
3. In vitro tests
4. Structure-activity analyses

Question 2

What is epidemiology?

Answer 2

The study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in defined populations.
The word epidemiology means “the study of what is upon the people”
epi – upon, among
demos – people/district
logos – study, word, discourse

Question 3

What is environmental epidemiology?

Answer 3

Concerned with determining how environmental exposures impact human health. It seeks to understand how various external risk factors may predispose to or protect against disease, illness, injury, developmental abnormalities, or death.

Question 4

What are the limits of what epidemiological studies can prove? Why?

Answer 4

• Epidemiological studies can only go to prove that an agent could have caused, but not that it did cause, an effect in any particular case. You can say “associated with”. Different than in animal studies that can prove causation.
• Because correlation is not causation. These studies can have confounding factors. Can try to reduce the amount of confounding factors by limiting variability by restricting studies to a subgroup or using regression models.

Question 5

What are confounding factors? Whats an example?

Answer 5

Occur when the study and control populations differ with respect to factors which might influence the occurrence of the disease.
For example, smoking might be a confounding factor and should be considered when designing studies for lungs and lung disease.

Question 6

What are the different types of Bias Errors?

Answer 6

• Selection bias
• Information bias
• Recall bias

Question 7

What is selection bias?

Answer 7

when the study group is not representative of the population from which it came.

Question 8

What is information bias?

Answer 8

when study subjects are misclassified as to disease or exposure status.

Question 9

What is recall bias?

Answer 9

individuals are asked to remember exposures or conditions that existed years before.

Question 10

What is probability and how is it calculated?

Answer 10

The likelihood that something will happen (%).

Probability = (# of positive events) / (# of positive events + # of negative events).

Question 11

What are odds and how is it calculated? What is the odds ratio, how is it calculated, and when is it used?

Answer 11

• Odds: The likelihood that something will happen compared to the likelihood that it will not happen.
  Odds = (# of positive events) / (# of negative events)
• Odds ratio: It is a ratio or proportion of odds.
  OR = Odds that the diseased were exposed / Odds the controls were exposed
  Used for case control studies (incidence of past exposure).

Question 12

What is the relative risk and how is it calculated? When is it used?

Answer 12

(RR) is is the ratio of probabilities expressed as a %.
Relative risk (RR) = Probability of getting disease if exposed / probability of getting disease if not exposed.
Used for Cohort studies and clinical trials.

Question 13

What happens if the RR=1, if its >1, if the OR=1, if its >1?

Answer 13

If RR or OR is equal to 1 then there is no difference between the groups. If they are more than one then it is harmful.

Question 14

What is a confidence interval? What if it’s above 1? below? crosses 1?

Answer 14

The confidence interval indicates the level of uncertainty around the measure of effect expressed as an odds ratio. Confidence intervals are used because a study recruits only a small sample of the overall population so by having an upper and lower confidence limit we can infer that the true population effect lies between these two points. Most studies report the 95% confidence interval (95% CI).
If the confidence interval crosses 1 (e.g. 95%CI 0.9-1.1) this implies there is no difference between arms of the study because 1 means there is no effect. If the intervals are above 1 then it means there is a significant increase in effect, if they are less than 1 then there is a significant decrease in effect.

Question 15

What are the different epidemiology types? What do you need in order to carry out a study?

Answer 15

You must have an ethics approval in order to carry out the study and in order to publish it.

• Experimental: The researcher intervenes and then observes what happens
• Observational: The researcher studies - but does NOT alter what occurs

Question 16

What is the typical flow & conditions of an experimental epidemiological trial? (L6S14)

Answer 16

It needs to be randomized, blinded, and all the confounding factors need to be considered.
All the steps with a * means there is a potential for introducing bias in the step.

1. Recruit participants
2. • Select participants to do the study on
3. • Allocation: separate the participants into an intervention group and a control group.
4. • Expose one group to the intervention and don’t expose the other.
5. • Follow up
6. • Outcome + Data collection
7. • Analysis

Question 17

Explain an experimental epidemiological trial done with canned beverages. Why is it an experimental trial?

Answer 17

Recruited 60 people and randomly split them into 3 groups of 20 to test the effect on the systolic BP after consuming 2 canned beverages: CC indicates 2 canned beverages; CG, 1 canned and 1 glass bottled beverages; GG indicates 2 glass bottled beverages.
Bisphenol A is the major can lining material. So the CC would in theory have more risk. They found there was an associated increase in systolic BP. by about 4.5 mm Hg after drinking from the 2 cans.
It’s experimental because the researcher is manipulating the independent variable (exposure to the BPA through cans) in order to observe the dependent variable (effect on blood pressure).

Question 18

What are the different types of epidemiology observational studies?

Answer 18

1. Cohort
2. Cross-sectional survey
3. Case control

Question 19

What is a cohort study? State the present and the future.

Answer 19

A cohort (group) of individuals with exposure to a chemical and a cohort without exposure are followed over time to compare disease occurrence.
Present: exposure
Future: disease

Question 20

What are the different types of cohort studies? explain them.

Answer 20

1. Prospective:
   At the time that I start looking, I don’t know the outcome. I will see effect later. I know one group was exposed and one wasn’t, and I’m going to look at what the outcome is after the exposure.
2. Retrospective:
   Looking at the end result (disease or not) and go backwards to see what the difference was between the groups.

Question 21

Explain the 2 different types of cohort studies by using the following study: Does in utero exposure to 13-cis retinoic-acid (accutane) adversely affect pregnancy outcome? Why is this a cohort study?

Answer 21

Cohorts: 154 human pregnancies with fetal exposure to isotretinoin (exposed) were compared to all infants born in Atlanta in 1982 (not exposed).

Outcomes:

• Retrospective: 95 elective abortions, 26 infants without major malformations, 12 spontaneous abortions, and 21 malformed infants.
• Prospective: 36 of the 154 pregnancies. The outcomes in this cohort were 8 spontaneous abortions, 23 normal infants, and 5 malformed infants.

Conclusion: Isotretinoin exposure was associated with an unusually high relative risk for a group of selected major malformations (relative risk = 25.6; 95 per cent confidence interval, 11.4 to 57.5). Usually the relative risk is 3%.
This is a cohort study because there are 2 groups: the exposed group (to accutane) and the non exposed group, the researcher does not have control over this variable. Then the researcher can observe the difference between the 2 groups either before the effect happens (prospective) or after the effect happens (retrospective).

Question 22

Explain the study: Does pre-natal and early childhood BPA exposure contribute to the development of obesity in children?
What are the possible confounding factors?
What kind of study is this and why?

Answer 22

BPA was measured in urine samples from pregnant women and children (at ages 3 and 5). Fat mass index (FMI) was assessed at ages 5 and 7.
Urinary BPA concentrations were positively associated with the child age 7 FMI (β = 0.31 kg/m2; 95% CI: 0.01, 0.60, p = 0.04). Therefore there was a relationship between BPA exposure and obesity.

Possible confounding factors:
The pregnant women could have been exposed to perfluorinated compounds too rather than just BPA, the mother could have a fast-food diet type, the children could have had a bad diet.

This is a prospective cohort study because they had no control over the independent variable (exposure to BPA), but the researcher then observed the effects of this exposure on children’s obesity (dependent variable) years later.

Question 23

What is a cross-sectional study? What is the present and future?

Answer 23

All factors (exposure, outcome, and confounders) of a population are measured simultaneously (at one specific point in time).
Present: Disease and exposure
Future: -

Question 24

Explain the study: Exposure of Young Men in Montreal to PBDEs (flame retardants) and Phthalates (plasticizers) and Reproductive Function. What kind of study is it and why?

Answer 24

153 healthy young men living in the greater Montreal area were exposed to polybrominated diphenyl ethers and phthalates therefore we studied their hormonal balance and semen quality.
How:
- A questionnaire
- Measured urinary phthalate metabolites
- Levels of PBDE in hair (to see when they were exposed)
- Took hormonal measurements
- Tested for semen and sperm chromatin quality

Results:

• Each 10-fold increase in BDE-47 (major flame retardant) was associated with lower TSH (thyroid funtion) levels (-17.3%; 95% CI: -31.5, 0.0; p = 0.05).
• BDE-47 exposure was also associated with a decrease in sperm concentration (-19.7%; 95% CI: -36.8; 2.0; p = 0.07) and motility (- 25.5%; 95% CI: -44.5, 0.1; p = 0.05).
• Trends towards decreases in these parameters were also observed in association with exposure to BDE-100 and the sum of BDE-47, -99, and -100 (∑3BDEs).
• Overweight men were more sensitive than men with a normal BMI to the endocrine disruptive effects of PBDEs.
• There were no differences with exposure to high phthalate levels vs low levels.

This is a cross sectional study because the exposure to PBDEs and Phthalates, their outcome (thyroid, sperm), and the confounders were all measured and observed at the same point in time.

Question 25

What is a case control study? State the present and past.

Answer 25

Individuals with a disease (such as cancer, a birth defect etc.) are compared with similar individuals without the disease to determine if there is an association of the disease with prior exposure to an agent.
Present: Disease
Past: exposure

Question 26

Where can you easily be exposed to flame retardants? What is a type of BFR?

Answer 26

It is usually measured from house dust because we are all exposed to it. Babies even more because they crawl.
Polybrominated diphenyl ethers (PBDEs) are a large group of flame retardants.

Question 27

In animal studies, what is PBDE shown to have an effect on?

Answer 27

In animal studies PBDEs disrupt sex hormones and adversely affect development of the reproductive system.

Question 28

What is cryptorchidism?

Answer 28

Nonsyndromic cryptorchidism is a common pediatric congenital anomaly, affects 2-3 % of boys; it is associated with infertility and testicular malignancy later in life. Testis descent is dependent on androgen exposure (such as testosterone) in utero.

Question 29

Explain the study done on cryptorchidism regarding flame retardants. What kind of study was it and why?

Answer 29

Question: Is there is a link between maternal hair PBDE levels and the risk of cryptorchidism in boys?
- If asking a question about a previous exposure: take piece of moms hair to measure what the exposure was at different times during pregnancy

Full term male children were recruited through clinics in Montreal, Toronto and London, Canada.
Boys with cryptorchidism at age 3-18 months (n=137) were identified by pediatric urologists and surgeons; similar-aged controls (n=158) had no genitourinary abnormalities. They then measured the PBDE exposure of the babies’ mothers by testing their hair. Then they plotted their results and adjusted for confounding factors (Odds ratios with a 95% CI Vs the different PBDEs). They found that Every 10-fold increase in maternal hair BDE-99 or BDE-100 was associated with more than a doubling in the risk of cryptorchidism. The association with BDE-154 is also significant. These three flame retardants were significant because their confidence intervals did NOT cross y=1

Conclusion:
PBDEs levels in maternal and child hair were highly correlated. So, baby was exposed to what mom was exposed to.

This is a case control study because babies with cryptorchidism were compared to similar babies without it in order to see if their mothers’ exposures to PBDEs differed and if that correlated with their disease.

Question 30

What is an ecological study?

Answer 30

The incidence of a disease in one geographical area is compared to that of another area, such as:
- Cancer mortality in areas with hazardous
waste sites as compared to similar areas
without waste sites
- The global burden of air pollution

Question 31

Explain the process of putting all of the evidence from different researchers for a specific question together (from the lowest point to the highest point). (S39)

Answer 31

7. Lowest: Background information/Expert opinion: get basic information

Unfiltered information:

6. Case-controlled studies (case series/reports: 1-2 cases)
7. Cohort studies
8. Randomized controlled trials (RCTs)

Filtered information: What was designed properly, done well, the right confounders and analysis were done, data might be re-analyzed.

3. Critically-appraised Individual Articles
4. Critically appraised topics
5. Systematic reviews: answers a specific question and defines how the review will be done and what the criteria is, what databases will be searched, and what languages will be included. Then publish criteria. And then THAT gets peer reviewed, and then you can do your systematic review based on these criteria.

Question 32

What is the process of a systematic review?

Answer 32

A recognized process for getting all of the pieces together for getting rid of bias and figuring out the real story.

1. Gather all of the records from databases and other sources: all possible sources that have to do with the topic you are reviewing
2. Remove any duplicates. Here you have a final # of records without duplicates.
3. Screen records for relevance and exclude records that are not relevant to the question you are asking
4. Assess the full-text articles for eligibility and provide reasoning for the ones you exclude. Ex: missing controls, didn’t do something properly
5. Only the studies that passed the tests of relevance and eligibility are included in the qualitative synthesis
6. and then in a quantitative synthesis (meta-analysis: statistical analysis of data across all of the relevant studies. Put the numbers together), if any.

Question 33

What is the anogenital distance (AGD)?

Answer 33

It is the distance from penis to anus. Boys have a larger AGD than girls due to androgen exposure in utero. Anogenital distance (AGD) is a marker for in utero testosterone exposure.

Question 34

Explain the systematic review and meta-analyses done for the effect of Dibutyl phthalate (plasticizer) on the AGD.

Answer 34

The question to be answered is: Does in utero exposure to dibutyl phthalate affect anogenital distance in male offspring?
In the systematic review of all of the studies relevant to this question, a meta-analyses were done in order to pool the data together and establish whether the different researchers have a consistent conclusion.

When they compared the data with their 95% confidence intervals, they saw that most of the confidence intervals were below 1 meaning that the AGD was decreasing with exposure to dibutyl phthalate. (3 studies had CIs that crossed 1).

Question 35

What is Trichloroethylene (TCE)? And how can you be exposed to it?

Answer 35

TCE is a high production volume chemical, a central nervous system depressant, a liver and kidney toxicant, and a human carcinogen.

Exposure:

• Occupational (high dose exposure): metal degreasing operations, dry-cleaning, sewage treatment plants, textile mills and other industries, releases from landfills, incinerators, septic tanks and storage tanks, and use and disposal of trichloroethylene- containing products (e.g., glues, paints)
• General population: ambient air, drinking water, contaminated food

Question 36

Explain the meta-analyses done on the TCE case-control studies.

Answer 36

TCE was a solvent used in military bases as a degreasing agent and it got into the ground water. The people noticed there was a high incidence of cancer with people living near the base. TCE makes a lot of reactive metabolites. The reactive chemicals can bind to proteins and DNA and lead to DNA damage to eventually cause cancer.
The meta-analyses combined the numerical data from multiple studies and concluded that there was a pretty consistent increase in kidney cancer in people exposed to high levels of TCE.

Conclusion: In 2021 they decided to compensate all of the people who got cancer that were still living because there was clear evidence that it was associated. They each got 62 000$.

Question 37

What is the hierarchy of evidence?

Answer 37

(9. Animal studies)
8. Editorials, expert opinion
7. Case report, case series
6. Ecological studies
5. Cross-sectional study
4. Case-control study
3. Cohort study
2. Randomized control trials
1. Systematic reviews