CONTRASTS AND INTERACTIONS

Transcription

1 (Italian ) Monsanto. Portugal! CONTRASTS AND INTERACTIONS BETWEEN EPIDEMIOLOGY AND TOXICOLOGY BRIEF COMMENTS Daniel A. Goldstein, M.D. Senior Science Fellow Lead, Medical Sciences and Outreach Monsanto Company St. Louis, Missouri, USA

2 RESOURCES A recent effort in this area: Adami et al ILSI-HESI WORKSHOP (PROCEEDINGS EXPECTED TO PUBLISH) 2

3 DISAGREEMENT EXPECTED Differences in exposure paradigm / relationship of exposure to range of biological relevance. Differences in measured outcomes / observed and observable features. Differences in degree of control for bias and confounding. Differences among species and strains Growing number of studies performing large number of comparisons HYPOTHESIS GENERATION IN THE CONTEXT OF LOW OUTCOME PROBABLITY. 3

4 TOXICOLOGY VS EPIDEMIOLOGY SENSIBLE to look at people to assess human effects. INTEREST in epidemiology much greater than toxicology! Early epidemiology DROVE development of modern toxicology Percivall Pott- scrotal cancer in chimney sweeps Yamagiwa and Ichikawa coal tar carcinogenesis on rabbit ear. BUT- we use toxicology based risk assessment WHY?? 4

5 EPIDEMIOLOGY DIFFICULT FOR MULTI-FACTORIAL OUTCOMES EASY HIGH velocity Lead Poisoning... NOT so easy LOW velocity Lead Poisoning... Hypertension Lead exposure Age Blood pressure Child Development Lead level Lead exposure Time Socioeconomics IQ Lead level 5 Parental Intellect

6 EPIDEMIOLOGY DIFFICULT DELAYED OR POORLY DEFINED OUTCOMES EASY Simple acute exposure Chemical Microbial Physical Seconds Hours Days Weeks Acute Outcome Illness Injury Death NOT so easy Remote / complex exposure Chronic Outcome Cancer Cognitive Chronic Lung Disease Reproductive, etc. Years or Decades Ill Defined Outcome Autism spectrum disorder Learning disability Parkinson s 6 Changing Ascertainment Changing criteria Changes in reporting

7 SOME HELP: BRADFORD-HILL CRITERIA Dose-Response Requires accurate assessment of BOTH exposure and outcome Time-Response Cause BEFORE effect (not always clear in retrospective study) Strength of Association Relatively large relative risk / odds ratio (>5) is strong Consistency Multiple studies in different and independent groups Specificity Exclusion of other causes or factors Biological Plausibility Established in large part via toxicology Coherence How does this fit the big picture? Weight of the Evidence 7

8 EXPOSURE- THE LARGEST PROBLEM. Irrational cluster or class: why should pesticides or herbicides, etc. be associated with ANY outcome?? Ever vs. Never exposed ( used ): reliability of recall is not clear, lumps exposure into a single point (no-dose-response), fails to establish differential exposure. Percent of individuals with detectable level: depends on analytical chemistry, not exposure, does not establish dose or differential exposure, no guarantee limit of detection is in relevant range. 8 Retrospective exposure scores: generally not validated, subject to recall bias, even if valid in relative sense, does not establish quantitative exposure for doseresponse.

9 EXPOSURE PROBLEMS. Use of metabolites: if form in environment, do not reflect exposure to parent compound, May have multiple sources. Limited sampling data: misses individual variation over time, data from one time (usually the present) may not reflect exposure at another time (usually the past) Clustering of exposure data (quartiles, high/medium/ low, etc.): data loss, differential or nondifferential misclassification. Missing data, imputation of data, or treatment of non-detectable values: undermines estimates of dose or effect. Ecological studies: fail to quantify individual exposure, subject to bias and confounding. 9

10 CAVEAT EMPTOR- FARM FAMILY EXPOSURE STUDY Monsanto produces glyphosate / participant in study. References- see supplemental slide at end One would ASSUME that farmers and farm family members sustain differential pesticide exposure related to application. IS THIS TRUE??? Wives Children ppb Glyphosate 2,4-D TCP ppb Glyphosate 2,4-D TCP 0 day -1 day 0 day 1 day 2 day 3 0 day -1 day 0 day 1 day 2 day 3 day of study day of study Geometric mean urine conc. Farmers Geometric mean urine conc ppb Glyphosate 2,4-D TCP 10 0 day -1 day 0 day 1 day 2 day 3 10 day of study Geometric mean urine conc. Total systemic dose (est.)

11 MEASURING OUTCOMES Quality of ascertainment Diagnostic assessment > Medical record > Self reported diagnosis Shifting, vague, or challenging diagnostic criteria Autism spectrum disorder / learning disability Cognitive deficits Fertility/fecundity/fetal loss rates, etc. Clustering of diagnoses Learning disability Malignancies- lung cancer, hematologic malignancy/leukemia/lymphoma, etc. Birth defects 11

12 12 BIAS / CONFOUNDING / ETC. Bias a systematic distortion introduced by methodology Recall bias Observer bias Healthy worker effect Selection bias Loss to follow-up Confounding- both the putative cause and the outcome relate via another independent variable that was not accounted for Model Error: Regression order in multiple regression analysis / selection and handling of covariants in ANOVA. Assumptions about the shape of underlying relationships can mask or create associations

13 13 MULTIPLE COMPARISONS AND HYPOTHESIS GENERATION Multiple possible causes: Individual pesticides Groups of pesticides- activity Groups of pesticides- structure Multiple health outcomes Multiple tumor types Everything else from wheezing to headaches Multiple subject categories Age, gender NEW ARENA- Genomics (10 million variants ) Multiple exposure metrics Estimate, tertile, quartile, quintile, etc Ever/never used, percent detectable, etc. An exploratory study can easily perform HUNDREDS or THOUSANDS of Comparisons

14 HYPOTHESIS GENERATION. Exploratory studies are usually billed as hypothesis generating studies raise QUESTIONS but cannot provide define causation. Increasingly easy to do and rewarding - they ALWAYS find associations. Confirmatory studies: Expensive, time consuming Unlikely to confirm hypothesis Not very attractive research Do NOT get done!! 14

15 TOXICOLOGY HAS LIMITATIONS TOO Species / Strain selection Cross species issues- Need for allometric scaling Differences in anatomy Differences in metabolism / ADME Differences in MoA Experimental mishaps or errors Lost/missing data Non-random sampling of animals Unwitnessed death / autolysis Diagnostic uncertainty (pathology) Differing routes of exposure Limited ability to assess certain outcomes (headache, depression) 15

16 MULTIPLE POINTS OF INTERFACE Weight of Evidence Approach to causation 16 Adami et al 2011

17 ADAMI ET AL PROPOSE A SCHEME WHICH HELPS TO CONCEPTUALIZE THE INTEGRATION PROCESS

18 CONCLUSIONS Epidemiology and Toxicology complementary when used thoughtfully in an integrated weight of evidence approach. Environmental epidemiology studies generally have serious weakness in exposure assessment. Other issues abound, but this appears to be the largest single problem. Multi-comparison exploratory studies are extremely attractive and increasingly easy to perform. but they generate QUESTIONS not answers 18

19 Turkey (male)- Monsanto St. Louis MY THANKS / OBRIGADO! 19

20 FFES REFERENCES Baker BA et al. Farm Family Exposure Study: methods and recruitment practices for a biomonitoring study of pesticide exposure. J Expo Anal Environ Epidemiol 2005; 15:491-9 Acquavella JF et al. Exposure misclassification in studies of agricultural pesticides. Epidemiology 2006; 17:69-74 Acquavella JF et al Glyphosate biomonitoring for farmers and their families: results from the farm family exposure study. Envir Health Perspectives 2004; 112:321-6 Alexander BH et al. Biomonitoring of 2,4-dichlorophenoxyacetic acid exposure in farm families. Envir Health Perspectives 2007; 115: Alexander BH et al. Chlorpyrifos exposure in farm families: results from the farm family exposure study. J Expo Sci Environ Epidemiol 2006; 16: Mandel JS et al Biomoniotoring for farm families in the farm family exposure study. Scand J Work Environ Health 2005; 31 Suppl 1: