Recent (and not so Recent) Methodological Issues in Environmental

Epidemiology Pam Factor-Litvak, PhD

Small Associations

So you know you are studying

epidemiology when… • Your professor says, “When I say smoking, you say

cancer”

• Professor: “Smoking”

• Class: “Cancer”

• Professor: “Smoking”

• Class: “Cancer”

• But these are the large associations….

Small Reductions in IQ: Shifts on the

Tails of the Distribution

www.environment.ucla.edu

Early Life Exposure to Lead

Defining the Shape of the Exposure – Response Curve

Lanphear et al 2005

Critical Periods of Exposure

What Matters? Timing of Exposure

Parsing Out Mixtures

Organochlorine Compounds, Thyroid

Function and Pregnancy Outcomes

Slight Differences in Structure

Make a Difference

DDT DDE

DDT and Birth Weight

Kezios et al 2013

Spearman correlation coefficients

among OH-PCBs and Parent PCBs.

4-OH-CB107 3’-OH-CB138 4-OH-CB146

PCB118 PCB138 PCB153 PCB187

rs=0.318

p<0.0001

rs =0.292

p<0.0001 rs =0.306

p<0.0001

rs =0.318

p<0.0001

rs =0.351

p<0.0001

rs =0.248

p<0.0001

3-OH-CB153 4-OH-CB187

Among smokers, covariate adjusted mean birth weight within quartiles both 4-OH-CB107 and PCB118 exposure, in a model mutually adjusted for the metabolite and its

parent PCB congener

Q1 Q2 Q3 Q4

4-OH-CB107 3437 3315 3247 3122

PCB 118 3163 3294 3229 3434

2900

3000

3100

3200

3300

3400

3500

3600

3700

3800

Bir

th w

eig

ht

(g)

Early Life Exposure to Phthalates

• 470 million pounds produced or imported in U.S. per

year

• Wildly used in consumer products

• High production chemicals with similar structures

• Exposures are ubiquitous in the U.S. and other

countries

Prenatal Postnatal Child age 7

Cohort = 328 African American & Dominican

mothers & children in Northern

Manhattan/South Bronx

Questionnaire

Medical record

Phthalates in

maternal 3rd

trimester urine

Questionnaire

Phthalates in child

age 3, 5, 7

urine

Wechsler Intelligence

Scale for Children, 4th

editions (WISC-IV)

Enrolled during pregnancy 1998-2006; excluded active smokers,

illicit drug users, women with HIV, hypertension or diabetes

Prenatal Exposure to Specific

Phthalates and Age 7 IQ Reductions

85

90

95

100

105

110

q0 q1 q2 q3 q0 q1 q2 q3 q0 q1 q2 q3

**p ≤ 0.01

7.6 ** 6.6 **

MnBP MiBP MBzP

Models controlled for maternal IQ, Home scale, child sex, race/ethnicity, maternal

prenatal alcohol consumption, education, marital status and specific gravity

*p < 0.05 **p ≤ 0.01

Postnatal Phthalates • Few associations between postnatal phthalates

and childhood IQ at age 7

• No changes in associations between any prenatal

phthalate and childhood IQ when postnatal

phthalates included in the model

Adding Up Mixtures

Rappaport 2011

PCBs and Time to Pregnancy

Results from Weighted Quantile

Approach with 1000 Bootstraps

Categories PCB congener Weights associated with

longer TTPa

Weights associated with

shorter TTPb

Bootstrap

Means

Average Bootstrap

Sum

Bootstrap

Means

Average

Bootstrap

Sum

Group 1:

Estrogenic

101 0.06

16%

0.10

17% 187c 0.01 0.07

201 0.09 0

Group 2A: Anti-estrogenic (AE), dioxin like

66 0.07

22%

0.02

46%

74 0.01 0.11

105d <0.01 0.08

118 0 0.12

156c 0.13 <0.01

167 0 0.12

Group 2B: AE & not dioxin like 138

d 0 <1%

0.06 14%

170 <0.01 0.07

Group 3: Phenobarb, CYP1A, CYP2B inducers

99c 0.02

9%

<0.01

23%

153 0 0.09

180 <0.01 0.04

203 <0.01 0.07

183d 0.07 0.02

Not categorized 56 0.47

54% <0.01

0 146 0.07 0

Mechanisms

Possible Mechanisms: Thyroid Function

Kahn et al 2014

Sex Specific Associations

Morgenstern et al 2017

Lessons Learned about Critical Periods

• Blood lead concentrations ‘tracked’ over

childhood; clearly associations with pre and post

natal exposures

• Urinary phthalate concentrations were not

correlated over time; associations clearly in

prenatal and possibly for one in postnatal period

• Organochlorine compounds are lipid soluble;

unfortunately we did not have repeated measures

in the childhood period

Opportunities • Small Associations

• Defining the Shape of the Dose Response Curve

• Parsing Out Mixtures

• Adding Up Mixtures

• Mechanisms

• Sex specific Associations

Acknowledgements

Acknowledgements • Barbara Cohn

• Piera Cirrillo • Teresa Janevic

• Matt Lamb

• Katrina Kezios

• Linda Kahn

• Keane Tsong

• Erica Lee

• Beverly Insel

• Rachelle Morgenstern

• Robin Whyatt • Julie Herbstman

• Megan Horton • Mary Kilty

• Joe Graziano

• Nancy LoIaconno • Gail Wasserman

• Vesna Slavkovich

• Duscan Popovac

• Jennie Kline

• Zena Stein

• Pat Shrout

• Xinhua Liu

• Pashko Camaj

• Chris Gennings • Katherine Keyes

• Ezra Susser • Myrto Petreas

Funding Sources: National Institute of Environmental Health Sciences, National Institute of Child Health and Development, US Environmental Protection Agency