Andrew G. Salmon

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 panels 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.

Evaluation and Application of the RD50 for Determining Acceptable Exposure Levels of Airborne Sensory Irritants for the General Public

Background The RD50 (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 (R2) between RD50s and the occupational exposure limits, particularly threshold limit values (TLVs). Objective The main purpose of this study was to examine the relationship between RD50s 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 RD50s 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 RD50s 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 RD50 in mice. Discussion We found the relationship between RD50s and LOAELs as log RD50 = 1.16 (log LOAEL) + 0.77 with an R2 value of 0.80. This strong correlation supports the use of the RD50 in establishing exposure limits for the public. We further identified 16 chemical irritants with both RD50s and corresponding acute RELs, and calculated the relationship as log RD50 = 0.71 (log REL) + 2.55 with an R2 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 RD50 has benefits for use in setting protective levels for the health of both workers and the general population.

Focusing on Children's Inhalation Dosimetry and Health Effects for Risk Assessment: An Introduction

Substantial effort has been invested in improving childrens health risk assessment in recent years. However, the body of scientific evidence in support of childrens health assessment is constantly advancing, indicating the need for continual updating of risk assessment methods. Childrens inhalation dosimetry and child-specific adverse health effects are of particular concern for risk assessment. When focusing on this topic within childrens health, key issues for consideration include (1) epidemiological evidence of adverse effects following childrens exposure to air pollution, (2) ontogeny of the lungs and effects on dosimetry, (3) estimation and variability of childrens 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 childrens inhalation dosimetry and adverse health effects for risk assessment. While much useful evidence is currently available, additional research and methods are warranted for improved childrens health risk assessment.

Does Haber's Law Apply to Human Sensory Irritation?

Irritation of the eyes, nose, and throat by airborne chemicals—also referred to as “sensory irritation”—is an important endpoint in both occupational and environmental toxicology. Modeling of human sensory irritation relies on knowledge of the physical chemistry of the compound(s) involved, as well as the exposure parameters (concentration and duration). A reciprocal relationship between these two exposure variables is postulated under Habers law, implying that protracted, low-level exposures may be toxicologically equivalent to brief, high-level exposures. Although time is recognized as having an influence on sensory irritation, the quantitative predictions of Habers Law have been addressed for only a handful of compounds in human experimental studies. We have conducted a systematic literature review that includes a semiquantitative comparison of psychophysical data extracted from controlled human exposure studies versus. the predictions of Habers law. Studies containing relevant data involved exposures to ammonia (2), chlorine (2), formaldehyde (1), inorganic dusts such as calcium oxide (1), and the volatile organic compound 1-octene (1). With the exception of dust exposure, varying exposure concentration has a proportionally greater effect on sensory irritation than does changing exposure duration. For selected time windows, a more generalized power law model (cn × t = k) rather than Habers law per se (c × t = k) yields reasonably robust predictions. Complicating this picture, however, is the frequent observation of intensity–time “plateauing,” with time effects disappearing, or even reversing, after a relatively short period, depending on the test compound. The implications of these complex temporal dynamics for risk assessment and standard setting have been incompletely explored to date.

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.

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 childrens 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 childrens 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.

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 EPAs 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.

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.

Development of California public health goals (PHGs) for chemicals in drinking water

As part of a program for evaluation of environmental contaminants in drinking water, risk assessments are being conducted to develop Public Health Goals (PHGs) for chemicals in drinking water, based solely on public health considerations. Californias Safe Drinking Water Act of 1996 mandated the development of PHGs for over 80 chemicals by 31 December 1999. The law allowed these levels to be set higher or lower than federal maximum contaminant levels (MCLs), including a level of zero if data are insufficient to determine a specific level. The estimated safe levels and toxicological rationale for the first 26 of these chemicals are described here. The chemicals include alachlor, antimony, benzo[a]pyrene, chlordane, copper, cyanide, dalapon, 1,2‐dichlorobenzene, 1,4‐dichlorobenzene, 2,4‐D, diethylhexylphthalate, dinoseb, endothall, ethylbenzene, fluoride, glyphosate, lead, nitrate, nitrite, oxamyl, pentachlorophenol, picloram, trichlorofluoromethane, trichlorotrifluoroethane, uranium and xylene(s). These risk assessments are to be considered by the State of California in revising and developing state MCLs for chemicals in drinking water (which must not exceed federal MCLs). The estimates are also notable for incorporation or consideration of newer guidelines and principles for risk assessment extrapolations. Copyright

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.