ObjectiveBradford Hill’s viewpoints were used to conduct a weight-of-the-evidence assessment of the association between Parkinson’s disease (PD) and rural living, farming and pesticide use. The results were compared with an assessment based upon meta-analysis. For comparison, we also evaluated the association between PD and cigarette smoking as a “positive control” because a strong inverse association has been described consistently in the literature.MethodsPubMed was searched systematically to identify all published epidemiological studies that evaluated associations between Parkinson’s disease (PD) and cigarette smoking, rural living, well-water consumption, farming and the use of pesticides, herbicides, insecticides, fungicides or paraquat. Studies were categorized into two study quality groups (Tier 1 or Tier 2); data were abstracted and a forest plot of relative risks (RRs) was developed for each risk factor. In addition, when available, RRs were tabulated for more highly exposed individuals compared with the unexposed. Summary RRs for each risk factor were calculated by meta-analysis of Tier 1, Tier 2 and all studies combined, with sensitivity analyses stratified by other study characteristics. Indices of between-study heterogeneity and evidence of reporting bias were assessed. Bradford Hill’s viewpoints were used to determine if a causal relationship between PD and each risk factor was supported by the weight of the evidence.FindingsThere was a consistent inverse (negative) association between current cigarette smoking and PD risk. In contrast, associations between PD and rural living, well-water consumption, farming and the use of pesticides, herbicides, insecticides, fungicides or paraquat were less consistent when assessed quantitatively or qualitatively.ConclusionThe weight of the evidence and meta-analysis support the conclusion that there is a causal relationship between PD risk and cigarette smoking, or some unknown factor correlated with cigarette smoking. There may be risk factors associated with rural living, farming, pesticide use or well-water consumption that are causally related to PD, but the studies to date have not identified such factors. To overcome the limitations of research in this area, future studies will have to better characterize the onset of PD and its relationship to rural living, farming and exposure to pesticides.

Chronic progressive nephropathy (CPN) is a spontaneous renal disease of rats which can be a serious confounder in toxicology studies. It is a progressive disease with known physiological factors that modify disease progression, such as high dietary protein. The weight of evidence supports an absence of a renal counterpart in humans. There is extensive evidence that advanced CPN, particularly end-stage kidney, is a risk factor for development of a background incidence of atypical tubule hyperplasia and renal tubule tumors (RTT). The likely cause underlying this association with tubule neoplasia is the long-term increased tubule cell proliferation that occurs throughout CPN progression. As a variety of chemicals are able to exacerbate CPN, there is a potential for those exacerbating the severity up to and including end-stage kidney to cause a marginal increase in RTT and their precursor lesions. Extensive statistical analysis of National Toxicology Program studies shows a strong correlation between high-grade CPN, especially end-stage CPN, and renal tumor development. CPN as a mode of action (MOA) for rat RTT has received attention from regulatory authorities only recently. In the absence of toxic effects elsewhere, this does not constitute a carcinogenic effect of the chemical but can be addressed through a proposed MOA approach for regulatory purposes to reach a decision that RTT, developing as a result of CPN exacerbation in rats, have no relevance for human risk assessment. Guidelines are proposed for evaluation of exacerbation of CPN and RTT as a valid MOA for a given chemical.

Ethylene oxide (EO) research has significantly increased since the 1980s, when regulatory risk assessments were last completed on the basis of the animal cancer chronic bioassays. In tandem with the new scientific understanding, there have been evolutionary changes in regulatory risk assessment guidelines, that encourage flexibility and greater use of scientific information. The results of an updated meta-analysis of the findings from 10 unique EO study cohorts from five countries, including nearly 33,000 workers, and over 800 cancers are presented, indicating that EO does not cause increased risk of cancers overall or of brain, stomach or pancreatic cancers. The findings for leukemia and non-Hodgkin's lymphoma (NHL) are inconclusive. Two studies with the requisite attributes of size, individual exposure estimates and follow up are the basis for dose-response modeling and added lifetime risk predictions under environmental and occupational exposure scenarios and a variety of plausible alternative assumptions. A point of departure analysis, with various margins of exposure, is also illustrated using human data. The two datasets produce remarkably similar leukemia added risk predictions, orders of magnitude lower than prior animal-based predictions under conservative, default assumptions, with risks on the order of 1 x 10(-6) or lower for exposures in the low ppb range. Inconsistent results for "lymphoid" tumors, a non-standard grouping using histologic information from death certificates, are discussed. This assessment demonstrates the applicability of the current risk assessment paradigm to epidemiological data.

Since cancer risk at very low doses cannot be directly measured in humans or animals, mathematical extrapolation models and scientific judgment are required. This article demonstrates a probabilistic approach to carcinogen risk assessment that employs probability trees, subjective probabilities, and standard bootstrapping procedures. The probabilistic approach is applied to the carcinogenic risk of formaldehyde in environmental and occupational settings. Sensitivity analyses illustrate conditional estimates of risk for each path in the probability tree. Fundamental mechanistic uncertainties are characterized. A strength of the analysis is the explicit treatment of alternative beliefs about pharmacokinetics and pharmacodynamics. The resulting probability distributions on cancer risk are compared with the point estimates reported by federal agencies. Limitations of the approach are discussed as well as future research directions.

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Estimating ecological risks associated with contaminants in the environment requires accurate characterization of the exposure of organisms to potentially toxic materials. Because organisms integrate contaminant exposure over space and time, estimating exposure concentrations reflective of actual exposures is a complex task. Quantification of spatial components of environmental exposure can utilize computerized Geographic Information Systems (GIS) as a central tool. The GIS was used to evaluate ecological risks to terrestrial receptors at a National Priorities List (NPL) site where dieldrin was one of the contaminants. The CIS was applied directly to estimating spatially weighted exposure concentrations within organisms' foraging, or exposure ranges. Moreover, CIS was also used for comparing exposure concentrations to "benchmark" concentrations and subsequent presentation of the results in a three-dimensional "risk surface" format. The three-dimensional risk surfaces were then superimposed on site-specific maps to serve as effective visual representations of site-specific quantified ecological risks and, as such, provide an effective risk-management decision-making tool. As an integral part of this approach, GIS serves as an interactive tool for assessing the effectiveness of proposed remedial alternatives by facilitating evaluation of effects of various remediation scenarios. This capability can be used to optimize remedial costs, benefits, and impacts.