Integrating Nonchemicals in Cumulative Risk Assessment (CRA): a A Case Study of Particulate Matter (PM) and Heart Rate Variability (HRV) Amanda M. Evans 1, Glenn E. Rice 2, Linda K. Teuschler 2, J. Michael Wright 2 1 Oak Ridge Institute for Science and Education 2 U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH

Acknowledgments This project was supported in part by an appointment to the Research Participation Program at the National Center for Environmental Assessment, Office of Research and Development, U.S. EPA, administered by the ORISE through an interagency agreement between the U.S. Department of Energy and U.S. EPA Disclaimer The views expressed herein are those of the authors and do not necessarily reflect of the views or policies of the U.S. EPA. 9 December 2013SRA 2013 Baltimore2

Outline 1.Define Cumulative Risk Assessment (CRA) 2.Discuss use of initiating factors in CRA 3.Review data on potentially vulnerable groups 4.Integrate diverse data using the Hazard Index 9 December 20133SRA 2013 Baltimore

Background: Cumulative Risk Assessment (CRA) EPA (2003) defines CRA as, “An analysis, characterization and possible quantification of the combined risks to health … from multiple … stressors”. Stressors can be chemicals (e.g., PM, Pb) or nonchemicals (e.g., noise) (EPA, 2003) 9 December 20134SRA 2013 Baltimore

Background: Nonchemical Factors and CRA CRAs also include an assessment of nonchemical factors that can increase or decrease vulnerability. Nonchemical factors can be related to genetics, underlying disease or nutritional status, psycho- social-economic, or lifestage  Distinction between nonchemical factors and stressors may be useful in some scenarios, it is not critical here (EPA, 2003; EPA, 2007; DeFur et al., 2007; Schwartz et al., 2011) 9 December 20135SRA 2013 Baltimore

Background: Identifying Relevant Nonchemicals Effect Measure Modification – the magnitude of the effect of an exposure of interest differs depending on the level of a third variable E.g., Disease associated with exposure in males but not in females – NOT CONFOUNDING 9 December 20136SRA 2013 Baltimore

a Sources, releases Population illness Integrated characterization Stressor concentrations Adapted from U.S. EPA, 2007 Data Elements Initiating Factors Background: Initiating Factors in CRA

Background: Heart Rate Variability (HRV) HRV is the physiological phenomenon of variation in the time interval between heartbeats. It is measured by the variation in the beat-to-beat interval. 9 December 20138SRA 2013 Baltimore  Low HRV is associated with a 32–45% increased risk of a first cardiovascular event in populations without known CVD (Hillebrand et al., 2013)

Background: HRV Measurement Time – SDNN (ms) = Standard deviation of all normal-to-normal interbeat intervals, reflects total variability 9 December 20139SRA 2013 Baltimore Frequency – HF = high frequency power (0.15 to 0.40 Hz), reflects parasympathetic activity Heart rate variability standards of measurement, physiological interpretation, and clinical use. (Malik M, et al. 1996)

Chemical Stressors associated with decreased HRV Air Pollution – Particulate Matter (PM 2.5) (Pieters et al., 2012) – Black Carbon (Hunag et al., 2013; Bartell et al., 2013) – Ozone (Romieu et al., 2013; Bartell et al., 2013) – Carbon Monoxide (Hunag et al., 2013; Bartell et al., 2013) – Organic Carbon (Bartell et al., 2013) – Volatile Organic Compounds (Mehta et al., 2012) Methyl mercury (Grandjean et al., 2004) Lead (Park et al., 2006) 9 December SRA 2013 Baltimore

Chemicals and Nonchemicals Affecting Decreased HRV Associated with PM 1.Multiple Chemical Stressors 2.Nonchemical Stressors 3.Pre-existing/Chronic Disease 4.Gene-Environment Interactions 9 December SRA 2013 Baltimore

Chemical Stressor: Chronic Pb 9 December SRA 2013 Baltimore *Adjusted for age, BMI, fasting blood glucose, antihypertensive medications (beta-blockers, calcium channel blockers, and ACE inhibitors), smoking, alcohol consumption, season (spring/summer/fall/winter), apparent temperature, mean arterial pressure, room temperature, educational attainment, and cumulative traffic Data from the Normative Aging Study including only elderly, White males. Park et al 2008

Nonchemical Stressor: Noise Huang et al *Adjusted for age, gender, BMI, hour of day, day of week, location (park vs. traffic center), temperature, relative humidity Data from a randomized, crossover study in Beijing, China among healthy young students (19-32 years of age) 9 December SRA 2013 Baltimore 2.1x lower than PM alone P for interaction <0.05

Park et al., 2010Data from MESA Study, participants 45–84 years old and free of CVD Nonchemical Factor: Disease Status 2.8x lower than PM alone Adjusted percent change in HRV (SDNN) for each 10.2 µg/m 3 of PM 2.5 by Metabolic Syndrome (MetS) Status PM 2.5 (10.2 µg/m 3 ), n=5,465 PM 2.5 (10.2 µg/m 3 ) & no MetS, n=3,698 PM 2.5 (10.2 µg/m 3 ) & MetS, N=1,768 9 December SRA 2013 Baltimore 0.3x higher than PM alone

Nonchemical Factor: Genetics Chahine et al., 2007 Data from the Normative Aging Study including only elderly, White males *GSTM=Glutathione S-transferase Mu 1, WT=wild type 1.4x lower 5x lower PM 2.5 (10 µg/m 3 ), n=539 PM 2.5 (10 µg/m 3 ) & GSTM WT, n=244 PM 2.5 (10 µg/m 3 ) & GSTM null, n=252 9 December SRA 2013 Baltimore

Nonchemical Factor: Diet Baccarelli et al 2008 *Adjusted for age, existing diagnosis of CHD, BMI, mean arterial pressure, fasting blood glucose, smoking, alcohol consumption, room temperature, apparent temperature, season, and use of -blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors Data from the Normative Aging Study including only elderly, White males 9 December SRA 2013 Baltimore PM 2.5 (10 µg/m 3 ), n=714 Vitamin B6 <3.65 mg/d, n=357 Vitamin B6 ≥3.65 mg/d, n=356 Vitamin B12 <11.1 µg/d, n=357 Vitamin B12 ≥11.1 µg/d, n=356 Methionine <1.88 g/d, n=352 Methionine ≥1.88 g/d, n= x lower 7.9x lower 1.7x lower 10.4x lower 1.7x lower 5.0x lower p-interaction=0.006p-interaction=0.01p-interaction=0.007

Nonchemical Factor: Diet Romieu et al 2005 *Adjusted for age, sex, HR, BMI, and hypertension Data from a randomized double-blind trial among 50 nursing home residents >60 years of age in Mexico City, Mexico 9 December SRA 2013 Baltimore 27x lower *p-interaction <0.01 Pre-PUFA Supplementation, n=26Post-PUFA Supplementation, n=26

HOW TO PUT IT ALL TOGETHER? 9 December SRA 2013 Baltimore

Based on dose addition, assuming toxicological similarity Interpreted as an indication of potential risk when HI > 1 U.S. EPA, 2000 Scaling factor = (1/RfV i ) for each stressor i n = total number of stressors causing the same effect RfV i is a Reference Value, representing an allowable level/intake of stressor i E i is estimated intake or exposure (in same units as the RfV i )  Use at levels/exposures where interaction effects are unlikely Hazard Index (HI) 9 December SRA 2013 Baltimore

CRA HI for HRV Particulate Matter (chemical stressor) Noise (nonchemical stressor) Lead (chemical stressor) Polyunsaturated fatty acid (nonchemical factor) 9 December SRA 2013 Baltimore PM Noise Pb PUFA

Considerations when using the HI for CRAs Values for various stressors and factors will often come from different data sources – Different populations, geographical areas, confounders Uncertainty how to interpret the HI – HI>1 can quickly be exceeded but there may or may not be any associated risk HI may not work well for some nonchemical factors – Dichotomous values (e.g., disease, genetics) – Variables with normal/optimal ranges (e.g., PUFAs) 9 December SRA 2013 Baltimore

What about those nonchemical factors… Populations possibly susceptible to decreased HRV associated with PM exposure include: – Metabolic Syndrome +, GSTM-null Ideally we would have: – Data on the combined effect of factors – Dose/exposure-response data specific for these susceptible populations and stressor/factor mixtures In lieu of this… – Their integration may only be qualitative 9 December SRA 2013 Baltimore

Reality is very complex…. 9 December SRA 2013 Baltimore

References Bartell, S. M., et al. (2013). "Particulate Air Pollution, Ambulatory Heart Rate Variability, and Cardiac Arrhythmia in Retirement Community Residents with Coronary Artery Disease." Environmental health perspectives. Chahine, T., et al. (2007). Particulate air pollution, oxidative stress genes, and heart rate variability in an elderly cohort. Environmental health perspectives,115(11), Hampel, R., et al. (2012). Acute air pollution effects on heart rate variability are modified by SNPs involved in cardiac rhythm in individuals with diabetes or impaired glucose tolerance. Environmental research, 112, Hillebrand, S., et al. (2013). Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: meta-analysis and dose–response meta-regression. Europace, 15(5), Huang, J., et al. (2013). The impacts of short-term exposure to noise and traffic-related air pollution on heart rate variability in young healthy adults. Journal of Exposure Science and Environmental Epidemiology. Malik M, Bigger JT, Camm AJ, Kleiger RE, Malliani A, Moss AJ, et al Heart rate variability standards of measurement, physiological interpretation, and clinical use. European heart journal 17: Park, S. K., et al. (2006). "HFE genotype, particulate air pollution, and heart rate variability: a gene-environment interaction." Circulation 114(25): Park, S. K., et al. (2008). "Air pollution and heart rate variability: effect modification by chronic lead exposure." Epidemiology 19(1): Park, S. K., et al. (2010). Particulate air pollution, metabolic syndrome, and heart rate variability: the multi- ethnic study of atherosclerosis (MESA). Environmental health perspectives, 118(10), Pieters N, Plusquin M, Cox B, Kicinski M, Vangronsveld J, Nawrot TS An epidemiological appraisal of the association between heart rate variability and particulate air pollution: A meta-analysis. Heart 98: Romieu, I., et al (2005). Omega-3 fatty acid prevents heart rate variability reductions associated with particulate matter. Am J Respir Crit Care Med, 172(12), doi: /rccm OC 9 December SRA 2013 Baltimore

Thank You! Questions, Thoughts, Suggestions… Contact Information: Amanda M Evans

Effect Modification of HRV dysregulation  Multiple Chemical Stressors Lead: HRV dysregulation associated with PM 2.5, sulfate, and ozone only at highest tibia Pb quartile (Park et al 2008)  Nonchemical Stressors Noise (>65 dBA), independently associated: increases HRV dysregulation associated with PM 2.5 (≈ 2-3x) and BC (≈2x) (Huang et al 2013)  Gene-Environment Interactions Hemochromatosis (HFE) polymorphisms (C282Y and H63D) associated with increased iron uptake, not independently associated: protective against PM 2.5 (Park et al 2006) – Increased iron uptake by cells in lung results in reduced oxidative stress and inflammation genetic modifiers (GSTM1 deletion and long repeats of HMOX-1 promoter) of response to oxidative stress (Chahine et al 2007)  Pre-existing/Chronic Disease Diabetes:  Prescription medication Angiotensin-converting enzyme (ACE) inhibitors 9 December SRA 2013 Baltimore

Effect Modification of PM 2.5 and HRV by a Nonchemical Factor-Disease Status Chen et al., 2007 Data from male boilerworkers in E. MA and free of CVD, mean age (years)= 39.5 ± 9.1, 1.6 x lower %Change in HRV (SDNN) Associated with a 1SD increase in PM 2.5 (10.2 µg/m 3 ) by Obesity Status 9 December SRA 2013 Baltimore

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Define Geographical Area 9 December SRA 2013 Baltimore

9 December 2013SRA 2013 Baltimore31 Malik M, Bigger JT, Camm AJ, Kleiger RE, Malliani A, Moss AJ, et al Heart rate variability standards of measurement, physiological interpretation, and clinical use. European heart journal 17:

9 December 2013SRA 2013 Baltimore32 Malik M et al

Interventions to increase HRV Pharmacological interventions associated with increased HRV and decreased mortality include: beta blockers without intrinsic sympathomimetic activity (ISA) post-MI ACE inhibitors and carvedilol in CHF sotalol in patients with ventricular arrhythmias estrogen replacement therapy in post-menopausal women  Smoking cessation  exercise training increases HRV in healthy older adults 9 December 2013SRA 2013 Baltimore33