Cancer risk: Role of environment Ashford, Nicholas A.; Bauman, Patricia; Brown, Halina S. ...
Science,
02/2015, Letnik:
347, Številka:
6223
Journal Article
Low-dose extrapolation model selection for evaluating the health effects of environmental pollutants is a key component of the risk assessment process. At a workshop held in Baltimore, Maryland, on ...23-24 April 2007, sponsored by U.S. Environmental Protection Agency and Johns Hopkins Risk Sciences and Public Policy Institute, a multidisciplinary group of experts reviewed the state of the science regarding low-dose extrapolation modeling and its application in environmental health risk assessments. Participants identified discussion topics based on a literature review, which included examples for which human responses to ambient exposures have been extensively characterized for cancer and/or noncancer outcomes. Topics included the need for formalized approaches and criteria to assess the evidence for mode of action (MOA), the use of human versus animal data, the use of MOA information in biologically based models, and the implications of interindividual variability, background disease processes, and background exposures in threshold versus nonthreshold model choice. Participants recommended approaches that differ from current practice for extrapolating high-dose animal data to low-dose human exposures, including categorical approaches for integrating information on MOA, statistical approaches such as model averaging, and inference-based models that explicitly consider uncertainty and interindividual variability.
Characterizing variability in the extent and nature of responses to environmental exposures is a critical aspect of human health risk assessment.
Our goal was to explore how next-generation human ...health risk assessments may better characterize variability in the context of the conceptual framework for the source-to-outcome continuum.
This review was informed by a National Research Council workshop titled "Biological Factors that Underlie Individual Susceptibility to Environmental Stressors and Their Implications for Decision-Making." We considered current experimental and in silico approaches, and emerging data streams (such as genetically defined human cells lines, genetically diverse rodent models, human omic profiling, and genome-wide association studies) that are providing new types of information and models relevant for assessing interindividual variability for application to human health risk assessments of environmental chemicals.
One challenge for characterizing variability is the wide range of sources of inherent biological variability (e.g., genetic and epigenetic variants) among individuals. A second challenge is that each particular pair of health outcomes and chemical exposures involves combinations of these sources, which may be further compounded by extrinsic factors (e.g., diet, psychosocial stressors, other exogenous chemical exposures). A third challenge is that different decision contexts present distinct needs regarding the identification-and extent of characterization-of interindividual variability in the human population.
Despite these inherent challenges, opportunities exist to incorporate evidence from emerging data streams for addressing interindividual variability in a range of decision-making contexts.
Background: Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are ...increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an "adverse effect" in the context of hazard identification and risk assessment. Objectives: Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. Discussion: Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. Conclusions: For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.
Background: Perchlorate is a common contaminant of drinking water and food. It competes with iodide for uptake into the thyroid, thus interfering with thyroid hormone production. The U.S. ...Environmental Protection Agency's Office of Solid Waste and Emergency Response (OSWER) set a groundwater preliminary remediation goal (PRG) of 24.5 µg/L to prevent exposure of pregnant women that would affect the fetus. This does not account for the greater exposure that is possible in nursing infants or for the relative source contribution (RSC), a factor normally used to lower the PRG due to nonwater exposures. Objectives: Our goal was to assess whether the OSWER PRG protects infants against exposures from breast-feeding, and to evaluate the perchlorate RSC. Methods: We used Monte Carlo analysis to simulate nursing infant exposures associated with the OSWER PRG when combined with background perchlorate. Results: The PRG can lead to a 7-fold increase in breast milk concentration, causing 90% of nursing infants to exceed the reference dose (RfD) (average exceedance, 2.8-fold). Drinking-water perchlorate must be < 6.9 µg/L to keep the median, and < 1.3 µg/L to keep the 90th-percentile nursing infant exposure below the RfD. This is 3.6- to 19-fold below the PRG. Analysis of biomonitoring data suggests an RSC of 0.7 for pregnant women and of 0.2 for nursing infants. Recent data from the Centers for Disease Control and Prevention (CDC) suggest that the RfD itself needs to be reevaluated because of hormonal effects in the general population. Conclusions: The OSWER PRG for perchlorate can be improved by considering infant exposures, by incorporating an RSC, and by being responsive to any changes in the RfD resulting from the new CDC data.
The Next Generation (NexGen) of Risk Assessment effort is a multi-year collaboration among several organizations evaluating new, potentially more efficient molecular, computational, and systems ...biology approaches to risk assessment. This article summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions.
Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures.
New data and methods were applied and evaluated for use in hazard identification and dose-response assessment. Biomarkers of exposure and effect, and risk characterization were also examined. Consideration was given to various decision contexts with increasing regulatory and public health impacts. Data types included transcriptomics, genomics, and proteomics. Methods included molecular epidemiology and clinical studies, bioinformatic knowledge mining, pathway and network analyses, short-duration in vivo and in vitro bioassays, and quantitative structure activity relationship modeling.
NexGen has advanced our ability to apply new science by more rapidly identifying chemicals and exposures of potential concern, helping characterize mechanisms of action that influence conclusions about causality, exposure-response relationships, susceptibility and cumulative risk, and by elucidating new biomarkers of exposure and effects. Additionally, NexGen has fostered extensive discussion among risk scientists and managers and improved confidence in interpreting and applying new data streams.
While considerable uncertainties remain, thoughtful application of new knowledge to risk assessment appears reasonable for augmenting major scope assessments, forming the basis for or augmenting limited scope assessments, and for prioritization and screening of very data limited chemicals. Citation: Cote I, Andersen ME, Ankley GT, Barone S, Birnbaum LS, Boekelheide K, Bois FY, Burgoon LD, Chiu WA, Crawford-Brown D, Crofton KM, DeVito M, Devlin RB, Edwards SW, Guyton KZ, Hattis D, Judson RS, Knight D, Krewski D, Lambert J, Maull EA, Mendrick D, Paoli GM, Patel CJ, Perkins EJ, Poje G, Portier CJ, Rusyn I, Schulte PA, Simeonov A, Smith MT, Thayer KA, Thomas RS, Thomas R, Tice RR, Vandenberg JJ, Villeneuve DL, Wesselkamper S, Whelan M, Whittaker C, White R, Xia M, Yauk C, Zeise L, Zhao J, DeWoskin RS. 2016. The Next Generation of Risk Assessment multiyear study-highlights of findings, applications to risk assessment, and future directions. Environ Health Perspect 124:1671-1682; http://dx.doi.org/10.1289/EHP233.
In his letter, Rhomberg raises several issues concerning recommendations in our report of the workshop "Issues and Approaches to Low Dose-Response Extrapolation for Environmental Health Risk ...Assessment" (White et al. 2009). One recommendation of the workshop was to set aside the generally held presumption that dose--response functions should follow a threshold model when extrapolating from higher dose studies of non-carcinogenic responses to lower dose levels typical for environmental exposures to chemicals. Workshop participants generally concluded that the selection of population-level low-dose extrapolation models should be informed by population factors such as interindividual variability in susceptibility and coexposures, as well as by categorization of mechanisms of toxicity. As indicated in the meeting report (White et al. 2009), most workshop participants preferred a linear, no-threshold approach to low-dose extrapolation modeling, combined with modeled estimates of the low range of observed data, for noncancer, as well as cancer, outcomes in the absence of convincing evidence to indicate that an alternative model is more appropriate. We recognize that this recommendation represents a departure from current generally accepted practice.
Role of smoking in low birth weight Magee, B Dale; Hattis, Dale; Kivel, Nancy M
Journal of reproductive medicine
49, Številka:
1
Journal Article
Recenzirano
To assess the role of smoking on low birth weight (LBW).
From Massachusetts for 1998, 79,904 birth certificates were reviewed. Birth weight, gestational age, plurality and maternal race were analyzed ...in relation to the mother's smoking status during the pregnancy. The etiologic fraction (EF) was calculated for smoking and LBW for the group as a whole as well as for various subgroups.
A total of 11.7% of women acknowledged smoking during pregnancy. The overall LBW rate was 6.83%. The relative risk (RR) of LBW among smokers was 1.58. For all births the EF for smoking was 6.4% (95% CI: 5.4-7.3). For singleton pregnancies it was 10.9% (95% CI: 9.6-12.1) (14% for singleton whites and 7.2 for singleton blacks). At term, the EF of smoking on LBW was 13.4% (95% CI: 11.5-15.3), with an EF of 16.7% (95% CI: 14.5-18.7) for term singletons (21.4% among whites and 14.6% among blacks). Among very LBW infants, smoking accounted for 1.7% (95% CI:--0.5-3.8) of the outcome (5.8% among singletons). When stratifying for the effect of smoking, the rate of LBW was 6.38% among nonsmokers, 9.5% (RR 1.48, 1.38-1.61) among light smokers, 11.67% (RR 1.82, 1.63-2.05) among moderate smokers and 11.72% (RR 1.84, 1.33-2.54) among heavy smokers. Sixty percent of the overall population effect of smoking on LBW was in the category of light smokers.
The amount of LBW attributable to smoking was 6.4% in this sample. Among those who smoked, LBW was 58% more likely than among nonsmokers, and 60% of the overall population effect of smoking on LBW was noted among light smokers.
Children's risks from environmental toxicant exposure can be affected by pharmacokinetic factors that affect the internal dose of parent chemical or active metabolite. There are numerous physiologic ...differences between neonates and adults that affect pharmacokinetics including size of lipid, and tissue compartments, organ blood flows, protein binding capacity, and immature function of renal and hepatic systems. These factors combine to decrease the clearance of many therapeutic drugs, which can also be expected to occur with environmental toxicants in neonates. The net effect may be greater or lesser internal dose of active toxicant depending upon how the agent is distributed, metabolized, and eliminated. Child/adult pharmacokinetic differences decrease with increasing postnatal age, but these factors should still be considered in any children's age group, birth through adolescence, for which there is toxicant exposure. Physiologically based pharmacokinetic (PBPK) models can simulate the absorption, distribution, metabolism, and excretion of xenobiotics in both children and adults, allowing for a direct comparison of internal dose and risk across age groups. This review provides special focus on the development of hepatic cytochrome
P-450 enzymes (CYPs) in early life and how this information, along with many factors unique to children, can be applied to PBPK models for this receptor population. This review describes a case study involving the development of neonatal PBPK models for the CYP1A2 substrates caffeine and theophylline. These models were calibrated with pharmacokinetic data in neonates and used to help understand key metabolic differences between neonates and adults across these two drugs.
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