Range of the perfluorooctanoate (PFOA) safe dose for human health: An international collaboration.

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.

The Conundrum of the PFOA human half-life, an international collaboration.

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.

The Dilemma of perfluorooctanoate (PFOA) human half-life.

Disparity 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.

Analysis for data-derived extrapolation factors for procymidone.

The derivation of Chemical Specific Adjustment Factors (CSAFs) (IPCS, 2005; U.S. EPA, 2014) depends on the choice of appropriate dose metric.

A commentary on some epidemiology data for chlorpyrifos.

Extensive 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.

Derivation of cancer no significant risk levels and screening safety assessment for 2-nitropropane in spray products.

Two proposition 65 no-significant-risk level (NSRL)-type values were derived for 2-nitropropane (2-NP), in the absence of a Californian published NSRL. In addition, a safety assessment was performed based on estimated typical consumer inhalation and dermal exposure to 2-NP during indoor application of paint from a spray can containing the solvent 1-nitropropane. For the NSRL derivation, benchmark dose (BMD) modeling was performed using hepatocellular carcinoma incidence data from 2-NP single exposure inhalation studies in Sprague-Dawley rats.

Data derived Extrapolation Factors for developmental toxicity: A preliminary research case study with perfluorooctanoate (PFOA).

Guidelines 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).

Managing risks of noncancer health effects at hazardous waste sites: A case study using the Reference Concentration (RfC) of trichloroethylene (TCE).

A 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.

A tiered asthma hazard characterization and exposure assessment approach for evaluation of consumer product ingredients.

Asthma is a complex syndrome with significant consequences for those affected. The number of individuals affected is growing, although the reasons for the increase are uncertain. Ensuring the effective management of potential exposures follows from substantial evidence that exposure to some chemicals can increase the likelihood of asthma responses.

Safety assessment for ethanol-based topical antiseptic use by health care workers: Evaluation of developmental toxicity potential.

Ethanol-based topical antiseptic hand rubs, commonly referred to as alcohol-based hand sanitizers (ABHS), are routinely used as the standard of care to reduce the presence of viable bacteria on the skin and are an important element of infection control procedures in the healthcare industry. There are no reported indications of safety concerns associated with the use of these products in the workplace. However, the prevalence of such alcohol-based products in healthcare facilities and safety questions raised by the U.

The importance of problem formulations in risk assessment: a case study involving dioxin-contaminated soil.

The need to remediate contaminated soils is typically accomplished by applying standard risk assessment methods followed by risk management to select remedial options. These human health risk assessments (HHRAs) have been largely conducted in a formulaic manner that relies heavily on standard deterministic exposure, toxicity assumptions and fixed mathematical formulas. The HHRA approach, with its traditional formulaic practice, does not take advantage of problem formulation in the same manner as is done in ecological risk assessment, and historically, has generally failed to emphasize incorporation of site-specific information.

Correlation of chemical structure with reproductive and developmental toxicity as it relates to the use of the threshold of toxicological concern.

In the absence of toxicological data on a chemical, the threshold of toxicological concern (TTC) approach provides a system to estimate a conservative exposure below which there is a low probability of risk for adverse health effects. The original toxicology dataset underlying the TTC was based on NOELs from repeat dose studies. Subsequently there have been several efforts to assess whether or not these limits are also protective for reproductive/developmental effects.

Efficacy of predictive modeling as a scientific criterion in dermal hazard identification for assignment of skin notations.

Skin notations (SNs) represent a hazard characterization tool for alerting workers of health hazards associated with dermal contact with chemicals. This study evaluated the efficacy of a predictive model utilized by the National Institute for Occupational Safety and Health to identify dermal hazards based on potential of systemic absorption compared to hazard assignments based on dermal lethal dose 50% or logarithm of octanol-water partition coefficient. A total of 480 chemicals assigned an SN from at least one of seven institutes were selected and partitioned into seven hazard categories by frequency of SN assignment to provide a basis of evaluation for the predictivity of the examined criteria.

The evolution of skin notations for occupational risk assessment: a new NIOSH strategy.

This article presents an overview of a strategy for assignment of hazard-specific skin notations (SK), developed by the National Institute for Occupational Safety and Health (NIOSH). This health hazard characterization strategy relies on multiple SKs capable of delineating systemic (SYS), direct (DIR), and immune-mediated (SEN) adverse effects caused by dermal exposures to chemicals. One advantage of the NIOSH strategy is the ability to combine SKs when it is determined that a chemical may cause multiple adverse effects following dermal contact (e.

Derived Reference Doses (RfDs) for the environmental degradates of the herbicides alachlor and acetochlor: results of an independent expert panel deliberation.

An independent peer expert panel was convened under the auspices of the Alliance for Risk Assessment (ARA) to review toxicology data and derive oral Reference Doses (RfDs) for four environmental degradates of the acetanilide herbicides, alachlor and acetochlor. The degradates included in this evaluation were (1) alachlor tertiary-ethanesulfonic acid (ESA), (2) alachlor tertiary-oxanilic acid (OXA), (3) acetochlor ESA, and (4) acetochlor OXA. Each degradate was judged to have sufficient data for developing low to medium confidence RfD, with use of an additional uncertainty factor (UF) to cover data gaps.

A review of the reference dose for chlorpyrifos.

Chlorpyrifos is an inhibitor of cholinesterase (ChE) and inhibition of ChE is believed to be the most sensitive effect in all animal species evaluated and in humans from previous evaluations. Recent literature, in particular epidemiology studies reporting associations between chlorpyrifos levels and fetal birth weight decreases, suggest the need to reevaluate the basis of the reference dose (RfD) for chlorpyrifos, however. In this paper, we evaluated newly available publications regarding chlorpyrifos toxicity and discuss the choice of critical effect--whether cholinesterase inhibition or developmental effect, the choice of appropriate species and study, the appropriate point of departure, and choice of uncertainty factors--including a discussion of the FQPA safety factor.

Lower birth weight as a critical effect of chlorpyrifos: a comparison of human and animal data.

Chlorpyrifos is an irreversible inhibitor of cholinesterase (ChE), and inhibition of ChE is believed to be the most sensitive effect in all animal species evaluated and in humans. Recent epidemiology studies reported associations between umbilical cord plasma chlorpyrifos levels and fetal birth weight decreases among minority women living in New York City during pregnancy. These associations raise questions whether impaired fetal development is the critical effect rather than the inhibition of ChE as is currently believed so.