Assessing health risks from multiple environmental stressors: Moving from G×E to I×E.

Research on disease causation often attempts to isolate the effects of individual factors, including individual genes or environmental factors. This reductionist approach has generated many discoveries, but misses important interactive and cumulative effects that may help explain the broad range of variability in disease occurrence observed across studies and individuals. A disease rarely results from a single factor, and instead results from a broader combination of factors, characterized here as intrinsic (I) and extrinsic (E) factors. Intrinsic vulnerability or resilience emanates from a variety of both fixed and shifting biological factors including genetic traits, while extrinsic factors comprise all biologically-relevant external stressors encountered across the lifespan. The I×E concept incorporates the multi-factorial and dynamic nature of health and disease and provides a unified, conceptual basis for integrating results from multiple areas of research, including genomics, G×E, developmental origins of health and disease, and the exposome. We describe the utility of the I×E concept to better understand and characterize the cumulative impact of multiple extrinsic and intrinsic factors on individual and population health. New research methods increasingly facilitate the measurement of multifactorial and interactive effects in epidemiological and toxicological studies. Tiered or indicator-based approaches can guide the selection of potentially relevant I and E factors for study and quantification, and exposomics methods may eventually produce results that can be used to generate a response function over the life course. Quantitative data on I×E interactive effects should generate a better understanding of the variability in human response to environmental factors. The proposed I×E concept highlights the role for broader study design in order to identify extrinsic and intrinsic factors amenable to interventions at the individual and population levels in order to enhance resilience, reduce vulnerability and improve health.

Association between Exposure to p,p'-DDT and Its Metabolite p,p'-DDE with Obesity: Integrated Systematic Review and Meta-Analysis.

BACKGROUND: The prevalence of obesity is increasing in all countries, becoming a substantial public health concern worldwide. Increasing evidence has associated obesity with persistent pollutants such as the pesticide DDT and its metabolite p,p'-DDE. OBJECTIVES: Our objective was to systematically review the literature on the association between exposure to the pesticide DDT and its metabolites and obesity to develop hazard identification conclusions. METHODS: We applied a systematic review-based strategy to identify and integrate evidence from epidemiological, in vivo, and in vitro studies. The evidence from prospective epidemiological studies was quantitatively synthesized by meta-analysis. We rated the body of evidence and integrated the streams of evidence to systematically develop hazard identification conclusions. RESULTS: We identified seven epidemiological studies reporting prospective associations between exposure to p,p'-DDE and adiposity assessed by body mass index (BMI) z-score. The results from the meta-analysis revealed positive associations between exposure to p,p'-DDE and BMI z-score (ß=0.13 BMI z-score (95% CI: 0.01, 0.25) per log increase of p,p'-DDE). Two studies constituted the primary in vivo evidence. Both studies reported positive associations between exposure to p,p'-DDT and increased adiposity in rodents. We identified 19 in vivo studies and 7 in vitro studies that supported the biological plausibility of the obesogenic effects of p,p'-DDT and p,p'-DDE. CONCLUSIONS: We classified p,p'-DDT and p,p'-DDE as "presumed" to be obesogenic for humans, based on a moderate level of primary human evidence, a moderate level of primary in vivo evidence, and a moderate level of supporting evidence from in vivo and in vitro studies. https://doi.org/10.1289/EHP527.

Active smoking and secondhand smoke increase breast cancer risk: the report of the Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk (2009).

Four authoritative reviews of active smoking and breast cancer have been published since 2000, but only one considered data after 2002 and conclusions varied. Three reviews of secondhand smoke (SHS) and breast cancer (2004-2006) each came to different conclusions. With 30 new studies since 2002, further review was deemed desirable. An Expert Panel was convened by four Canadian agencies, the Ontario Tobacco Research Unit, the Public Health Agency of Canada, Physicians for a Smoke-Free Canada and the Canadian Partnership Against Cancer to comprehensively examine the weight of evidence from epidemiological and toxicological studies and understanding of biological mechanisms regarding the relationship between tobacco smoke and breast cancer. This article summarises the panel's full report (http://www.otru.org/pdf/special/expert_panel_tobacco_breast_cancer.pdf). There are 20 known or suspected mammary carcinogens in tobacco smoke, and recognised biological mechanisms that explain how exposure to these carcinogens could lead to breast cancer. Results from the nine cohort studies reporting exposure metrics more detailed than ever/never and ex/current smoker show that early age of smoking commencement, higher pack-years and longer duration of smoking increase breast cancer risk 15% to 40%. Three meta-analyses report 35% to 50% increases in breast cancer risk for long-term smokers with N-acetyltransferase 2 gene (NAT2) slow acetylation genotypes. The active smoking evidence bolsters support for three meta-analyses that each reported about a 65% increase in premenopausal breast cancer risk among never smokers exposed to SHS. The Panel concluded that: 1) the association between active smoking and breast cancer is consistent with causality and 2) the association between SHS and breast cancer among younger, primarily premenopausal women who have never smoked is consistent with causality.

Inhalation of an essential metal: development of reference exposure levels for manganese.

Exposures to high levels of manganese by ingestion or inhalation can damage the central nervous system. However, the capacity of environmental manganese to cause neurotoxicity is of most concern following inhalation exposure. Reference exposure levels (RELs) are values developed by California EPA's Office of Environmental Health Hazard Assessment (OEHHA) to protect the general public from periodic and continual exposures to airborne toxicants. The recently revised guidelines for the development of noncancer RELs encourage the use of benchmark dose methodology where appropriate, and explicitly address the potential susceptibilities associated with early-life exposures (OEHHA, 2008). This paper describes the application of those guidelines to the derivation of RELs to protect the general public from routine 8h and chronic exposures to airborne manganese. The data were amenable to benchmark analysis and the RELs derived reflect the mounting evidence that children represent a population that is differentially susceptible to manganese toxicity.

Development of TEFs for PCB congeners by using an alternative biomarker--thyroid hormone levels.

Polychlorinated biphenyls (PCBs) are ubiquitous toxic contaminants. Health risk assessment for this class of chemicals is complex: the current toxic equivalency factor (TEF) method covers dioxin-like (DL-) PCBs, dibenzofurans, and dioxins, but excludes non-DL-PCBs. To address this deficiency, we evaluated published data for several PCB congeners to determine common biomarkers of effect. We found that the most sensitive biomarkers for DL-non-ortho-PCB 77 and PCB 126 are liver enzyme (e.g., ethoxyresorufin-O-deethylase, EROD) induction, circulating thyroxine (T4) decrease, and brain dopamine (DA) elevation. For DL-ortho-PCB 118 and non-DL-ortho-PCB 28 and PCB 153, the most sensitive biomarkers are brain DA decrease and circulating T4 decrease. The only consistent biomarker for both DL- and non-DL-PCBs is circulating T4 decrease. The calculated TEF-(TH), based on the effective dose to decrease T4 by 30% (ED(30)) with reference to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is identical to both TEF-(WHO98) and TEF-(WHO05) for TCDD and DL-PCBs (correlation coefficients are r=1.00, P<0.001; and r=0.99, P<0.001, respectively). We conclude that T4 decrease is a prospective biomarker for generating a new TEF scheme which includes some non-DL-congeners. The new TEF-(TH) parallels the TEF-(WHO) for DL-PCBs and, most importantly, is useful for non-DL-PCBs in risk assessment to address thyroid endocrine disruption and potentially the neurotoxic effects of PCBs.

Do standard risk assessment procedures adequately account for cumulative risks?: an exploration of the possibilities using California's Air Toxics Hot Spots guidelines.

Existing risk assessment data and procedures can be used to address the estimation of cumulative risk, but there are several uncertainties. These are explored in the context of the State of California's Air Toxic Hot Spots program. Hazard identification for single agents is an established procedure but is much more complex for incompletely characterized or variable mixtures. Hazards from exposure to multiple agents are often only identified by chance. Similar concerns affect dose-response assessment. Although additivity is assumed by default for similar effects at low doses, exceptions are known for specific mixtures and for higher dose rates. Exposure assessment is especially complex for multiple sources, multiple agents from different sources, and target populations or individuals who face cumulative, but not necessarily simultaneous, impacts. With these contributory uncertainties, providing an integrated analysis that can inform risk management and presenting this to a diverse and often already stressed community are challenging.

Focusing on children's inhalation dosimetry and health effects for risk assessment: an introduction.

Substantial effort has been invested in improving children's health risk assessment in recent years. However, the body of scientific evidence in support of children's health assessment is constantly advancing, indicating the need for continual updating of risk assessment methods. Children's inhalation dosimetry and child-specific adverse health effects are of particular concern for risk assessment. When focusing on this topic within children's health, key issues for consideration include (1) epidemiological evidence of adverse effects following children's exposure to air pollution, (2) ontogeny of the lungs and effects on dosimetry, (3) estimation and variability of children's inhalation rates, and (4) current risk assessment methodologies for addressing children. In this article, existing and emerging information relating to these key issues are introduced and discussed in an effort to better understand children's inhalation dosimetry and adverse health effects for risk assessment. While much useful evidence is currently available, additional research and methods are warranted for improved children's health risk assessment.

Potential new approaches for children's inhalation risk assessment.

The U.S. Environmental Protection Agency (EPA) practice of risk assessment is moving toward more thoroughly considering children's unique susceptibilities and exposure potential. Childhood is assessed as a sequence of life stages that reflects the fact that as humans develop, windows of susceptibility may appear that lead to enhanced sensitivity to exposure of environmental agents, while changes in behavior and physiology may increase exposure and dose. The U.S. EPA developed guidance in the past few years that addresses some aspects of increased susceptibility and exposure and dose. However, when it comes to considering inhalation exposure, dose, and risk, current U.S. EPA practice does not explicitly address children. The purpose here is to begin studying the adequacy of practice for children's health and to explore possible next steps in developing new methods to more accurately assess life-stage-specific differences. The existing guidelines and policies used to address potentially unique susceptibilities of children for inhaled environmental chemicals were considered, as well as what may be learned from examples of approaches that have been applied by state agencies (such as the California Environmental Protection Agency) or in the literature, to incorporate potentially unique susceptibilities and exposures to children. Finally, there is a discussion of possible approaches for considering inhalation exposure and susceptibility in U.S. EPA risk assessments.

Evaluation and application of the RD50 for determining acceptable exposure levels of airborne sensory irritants for the general public.

BACKGROUND: The RD(50) (exposure concentration producing a 50% respiratory rate decrease) test evaluates airborne chemicals for sensory irritation and has become an American Society for Testing and Materials (ASTM) standard method. Past studies reported good correlations (R(2)) between RD(50)s and the occupational exposure limits, particularly threshold limit values (TLVs). OBJECTIVE: The main purpose of this study was to examine the relationship between RD(50)s and human sensory irritation responses in a quantitative manner, particularly for chemicals that produce burning sensation of the eyes, nose, or throat, based on lowest observed adverse effect levels (LOAELs) reported for human subjects. METHODS: We compared RD(50)s with LOAELs and acute reference exposure levels (RELs). RELs, developed by the California Environmental Protection Agency's Office of Environmental Health Hazard Assessment, represent a level at which no adverse effects are anticipated after exposure. We collected RD(50)s from the published literature and evaluated them for consistency with ASTM procedures. We identified LOAELs for human irritation and found 25 chemicals with a corresponding RD(50) in mice. DISCUSSION: We found the relationship between RD(50)s and LOAELs as log RD(50) = 1.16 (log LOAEL) + 0.77 with an R(2) value of 0.80. This strong correlation supports the use of the RD(50) in establishing exposure limits for the public. We further identified 16 chemical irritants with both RD(50)s and corresponding acute RELs, and calculated the relationship as log RD(50) = 0.71 (log REL) + 2.55 with an R(2) value of 0.71. This relationship could be used to identify health protective values for the public to prevent respiratory or sensory irritation. CONCLUSION: Consequently, we believe that the RD(50) has benefits for use in setting protective levels for the health of both workers and the general population.

The association between exposure to environmental tobacco smoke and breast cancer: a review by the California Environmental Protection Agency.

BACKGROUND: The California Environmental Protection Agency (Cal/EPA) recently completed a health effects assessment of exposure to environmental tobacco smoke (ETS) which resulted in California listing ETS as a Toxic Air Contaminant in January 2006. As part of the assessment, studies on the association between exposure to ETS and breast cancer were reviewed. METHODS: Twenty-six published reports (including 3 meta-analyses) evaluating the association between ETS exposure and breast cancer were reviewed. A weight-of-evidence approach was applied to evaluate the data and draw conclusions about the association between breast cancer and ETS exposure. RESULTS: The published data indicate an association between ETS and breast cancer in younger primarily premenopausal women. Thirteen of 14 studies (10 case-control and four cohort) that allowed analysis by menopausal status reported elevated risk estimates for breast cancer in premenopausal women, seven of which were statistically significant. Our meta-analyses indicated elevated summary relative risks ranging from OR 1.68 (95% C.I. 1.31, 2.15) for all 14 studies to 2.20 (95% C.I. 1.69, 2.87) for those with the best exposure assessment. CONCLUSIONS: Cal/EPA concluded that regular ETS exposure is causally related to breast cancer diagnosed in younger, primarily premenopausal women and that the association is not likely explained by bias or confounding.

Development of a chronic inhalation reference level for respirable crystalline silica.

Chronic inhalation exposure of workers to crystalline silica can result in silicosis. The general public can also be exposed to lower levels of crystalline silica from quarries, sand blasting, and entrained fines particles from surface soil. We have derived an inhalation chronic reference exposure level for silica, a level below which no adverse effects due to prolonged exposure would be expected in the general public. Incidence of silicosis and silica exposure data from a cohort of 2235 white South African gold miners yielded a reference level of 3 microg/m3) for respirable silica (particle size as defined occupationally) using a benchmark concentration approach. Data from cohorts of American gold miners, Chinese tin miners, diatomaceous earth workers, and black South African gold miners yielded similar results with a range of 3-10 microg/m3. Strengths of the chronic reference exposure level include the availability of several large long-term studies of inhalation in workers at varying exposure concentrations, adequate histopathological and radiologic analysis, adequate follow-up of exposed workers, a dose-response effect in several studies, observation of a No Observed Adverse Effect Level in the key study, and the power of the key study to detect a small effect. Uncertainties include the general underestimation of silicosis by radiography alone and the uncertainties in exposure estimation.

Acute toxicity and cancer risk assessment values for tert-butyl acetate.

tert-Butyl acetate (TBAc) is an industrial chemical with potential uses as a degreaser and in architectural coatings. Limited chronic toxicity data exist for TBAc. However, acute inhalation exposure data are available for TBAc. Additionally, TBAc has been demonstrated to be substantially metabolized to tert-butanol (TBA) in rats, and a positive TBA genotoxicity study suggests that TBA may cause oxidative DNA damage. TBA has been shown to induce tumors in both rats and mice, and the Office of Environmental Health Hazard Assessment has calculated an oral cancer potency factor (CSF) for TBA of 3 x 10(-3)(mg/kg-day)(-1). Therefore, TBAc should be considered to pose a potential cancer risk to humans because of the metabolic conversion to TBA. An acute 1-h reference exposure level of 1 mg/m3 can be calculated from the extrapolated no observed adverse effect level of 50 mg/m3. A CSF of 0.002(mg/kg-day)(-1) can be derived for TBAc, assuming 100% metabolism of TBAc to TBA. An inhalation unit risk value for TBAc of 4 x 10(-7)(microg/m(3))(-1) can then be derived from the CSF value for TBAc by assuming a human breathing rate of 20 m3/day, 70% fractional absorption, and an average human body weight of 70 kg.