Many government agencies and expert groups have estimated a dose-rate of perfluorooctanoate (PFOA) that would protect human health. Most of these evaluations are based on the same studies (whether of humans, laboratory animals, or both), and all note various uncertainties in our existing knowledge. Nonetheless, the values of these various, estimated, safe-doses vary widely, with some being more than 100,000 fold different.
View Article and Find Full Text PDFRegul Toxicol Pharmacol
July 2022
The Steering Committee of the Alliance for Risk Assessment (ARA) opened a call for scientists interested in resolving what appeared to be a conundrum in estimating of the half-life of perfluorooctanoate (PFOA) in humans. An Advisory Committee was formed from nominations received and a subsequent invitation led to the development of three small independent working groups to review appropriate information and attempt a resolution. Initial findings were shared among these groups and a conclusion developed from the ensuing discussions.
View Article and Find Full Text PDFThe Delaney Clause of the Federal Food, Drug, and Cosmetic Act became law in 1958 because of concerns that potentially harmful chemicals were finding their way into foods and causing cancer. It states, "[n]o additive shall be deemed to be safe if it is found to induce cancer when ingested by man or animal, or if it is found, after tests which are appropriate for the evaluation of the safety of food additives, to induce cancer in man or animal." The United States Food and Drug Administration (US FDA) and United States Environmental Protection Agency (US EPA, prior to implementation of the Food Quality Protection Act) were charged with implementing this clause.
View Article and Find Full Text PDFDisparity in the results from human observational and clinical studies is not uncommon, but risk assessment efforts often judge one set of data more relevant with the loss of valuable information. The assessment for perfluorooctanoate (PFOA) is a good example of this problem. The estimation of its safe dose is disparate among government groups due in part to differences in understanding of its half-life in humans.
View Article and Find Full Text PDFRegul Toxicol Pharmacol
August 2021
The derivation of Chemical Specific Adjustment Factors (CSAFs) (IPCS, 2005; U.S. EPA, 2014) depends on the choice of appropriate dose metric.
View Article and Find Full Text PDFMany state and federal environmental and health agencies have developed risk-based criteria for assessing the risk of adverse health effects of per- and polyfluorinated alkyl substances (PFAS) exposure to humans and the environment. However, the criteria that have been developed vary; drinking water criteria developed for perfluorooctanoic acid, for example, can vary by up to 750 fold. This is due to differences and variability in the data and information used, study/endpoint selection, assumptions and magnitude of uncertainty factors used in the absence and extrapolation of critical effect data, differences in underlying approaches to addressing exposure within criteria development, and/or policy decisions on levels of acceptable risk.
View Article and Find Full Text PDFExtensive animal and human studies on chlorpyrifos (CPF) point to changes in a blood enzyme as its first biological effect, and governments and health groups around the world have used this effect in the determination of its safe dose. Preventing this first biological effect, referred to in risk assessment parlance as the critical effect, is part and parcel of chemical regulation in general and of CFP specifically. Rauh et al.
View Article and Find Full Text PDFBased on the wide use of cobalt substances in a range of important technologies, it has become important to predict the toxicological properties of new or lesser-studied substances as accurately as possible. We studied a group of 6 cobalt substances with inorganic ligands, which were tested for their bioaccessibility (surrogate measure of bioavailability) through in vitro bioelution in simulated gastric and intestinal fluids. Representatives of the group also underwent in vivo blood kinetics and mass balance tests, and both oral acute and repeated dose toxicity (RDT) testing.
View Article and Find Full Text PDFGuidelines of the United States Environmental Protection Agency (EPA, 1991) and the International Programme on Chemical Safety (IPCS, 2005) suggest two different default positions for dosimetric extrapolation from experimental animals to humans when the dosimetry of the critical effect is not known. The default position of EPA (1991) for developmental toxicity is to use peak concentration (or Cmax) for this dosimetric extrapolation. In contrast, IPCS (2005, page 39) states its default position for dosimetric choice in the absence of data is to use the area under the curve (or AUC).
View Article and Find Full Text PDFRegul Toxicol Pharmacol
August 2018
The Integrated Risk Information System (IRIS) of the U.S. Environmental Protection Agency (EPA) has an important role in protecting public health.
View Article and Find Full Text PDFBenchmark dose (BMD) modeling is now the state of the science for determining the point of departure for risk assessment. Key advantages include the fact that the modeling takes account of all of the data for a particular effect from a particular experiment, increased consistency, and better accounting for statistical uncertainties. Despite these strong advantages, disagreements remain as to several specific aspects of the modeling, including differences in the recommendations of the US Environmental Protection Agency (US EPA) and the European Food Safety Authority (EFSA).
View Article and Find Full Text PDFPrevious work has shown that the weight of evidence supports the hypothesis that 1,4-dioxane causes liver tumors in rodents through cytotoxicity and subsequent regenerative hyperplasia. Questions regarding a lack of concordant findings for this mode of action (MOA) in mice have not been resolved, however. In the current work, a reanalysis of data from two chronic mouse cancer bioassays on 1,4-dioxane, one 13-week mouse study, seven rat cancer bioassays, coupled with other data such as 1,4-dioxane's negative mutagenicity, its lack of up-regulated DNA repair, and the appearance of liver tumors with a high background incidence, support the conclusion that rodent liver tumors, including those in mice, are evoked by a regenerative hyperplasia MOA.
View Article and Find Full Text PDFThe evolved World Health Organization/International Programme on Chemical Safety mode of action (MOA) framework provides a structure for evaluating evidence in pathways of causally linked key events (KE) leading to adverse health effects. Although employed globally, variability in use of the MOA framework has led to different interpretations of the sufficiency of evidence in support of hypothesized MOAs. A proof of concept extension of the MOA framework is proposed for scoring confidence in the supporting data to improve scientific justification for MOA use in characterizing hazards and selecting dose-response extrapolation methods for specific chemicals.
View Article and Find Full Text PDFJ Air Waste Manag Assoc
November 2016
Petroleum coke or "petcoke" is a solid material created during petroleum refinement and is distributed via transfer facilities that may be located in densely populated areas. The health impacts from petcoke exposure to residents living in proximity to such facilities were evaluated for a petcoke transfer facilities located in Chicago, Illinois. Site-specific, margin of safety (MOS) and margin of exposure (MOE) analyses were conducted using estimated airborne and dermal exposures.
View Article and Find Full Text PDFThe safety of food ingredients will be assessed in the 21st century by mixture of traditional methods, such as the "safe" dose concept, which is thought to be an accurate but imprecise estimation of dose below the population threshold for adverse effect, and contemporary methods, such as the Benchmark Dose (BMD), Chemical Specific Adjustment Factors (CSAF), physiologically-based pharmacokinetic models, and biologically-informed dose response modeling. New research on the horizon related to toxicology 21 may also improve these risk assessment methods, or suggest new ones. These traditional, contemporary and new methods and research will be briefly described.
View Article and Find Full Text PDFA method for determining a safety range for non-cancer risks is proposed, similar in concept to the range used for cancer in the management of waste sites. This safety range brings transparency to the chemical specific Reference Dose or Concentration by replacing their "order of magnitude" definitions with a scientifically-based range. EPA's multiple RfCs for trichloroethylene (TCE) were evaluated as a case study.
View Article and Find Full Text PDFRegul Toxicol Pharmacol
October 2016
In 2014, the National Research Council (NRC) published Review of EPA's Integrated Risk Information System (IRIS) Process that considers methods EPA uses for developing toxicity criteria for non-carcinogens. These criteria are the Reference Dose (RfD) for oral exposure and Reference Concentration (RfC) for inhalation exposure. The NRC Review suggested using Bayesian methods for application of uncertainty factors (UFs) to adjust the point of departure dose or concentration to a level considered to be without adverse effects for the human population.
View Article and Find Full Text PDFEnviron Int
November 2016
Single point estimates of human health hazard/toxicity values such as a reference dose (RfD) are generally used in chemical hazard and risk assessment programs for assessing potential risks associated with site- or use-specific exposures. The resulting point estimates are often used by risk managers for regulatory decision-making, including standard setting, determination of emission controls, and mitigation of exposures to chemical substances. Risk managers, as well as stakeholders (interested and affected parties), often have limited information regarding assumptions and uncertainty factors in numerical estimates of both hazards and risks.
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