10-fold Uncertainty Research Articles

Bayesian Analysis of Silica Exposure and Lung Cancer Using Human and Animal Studies.

Bayesian methods can be used to incorporate external information into epidemiologic exposure-response analyses of silica and lung cancer. We used data from a pooled mortality analysis of silica and lung cancer (n = 65,980), using untransformed and log-transformed cumulative exposure. Animal data came from chronic silica inhalation studies using rats. We conducted Bayesian analyses with informative priors based on the animal data and different cross-species extrapolation factors. We also conducted analyses with exposure measurement error corrections in the absence of a gold standard, assuming Berkson-type error that increased with increasing exposure. The pooled animal data exposure-response coefficient was markedly higher (log exposure) or lower (untransformed exposure) than the coefficient for the pooled human data. With 10-fold uncertainty, the animal prior had little effect on results for pooled analyses and only modest effects in some individual studies. One-fold uncertainty produced markedly different results for both pooled and individual studies. Measurement error correction had little effect in pooled analyses using log exposure. Using untransformed exposure, measurement error correction caused a 5% decrease in the exposure-response coefficient for the pooled analysis and marked changes in some individual studies. The animal prior had more impact for smaller human studies and for one-fold versus three- or 10-fold uncertainty. Adjustment for Berkson error using Bayesian methods had little effect on the exposure-response coefficient when exposure was log transformed or when the sample size was large. See video abstract at, http://links.lww.com/EDE/B160.

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

The acceptable daily intake (ADI) of commercially available steviol glycosides is currently 0–4 mg/kg body weight (bw)/day, based on application of a 100-fold uncertainty factor to a no-observed-adverse-effect-level value from a chronic rat study. Within the 100-fold uncertainty factor is a 10-fold uncertainty factor to account for inter-species differences in toxicokinetics (4-fold) and toxicodynamics (2.5-fold). Single dose pharmacokinetics of stevioside were studied in rats (40 and 1000 mg/kg bw) and in male human subjects (40 mg/kg bw) to generate a chemical-specific, inter-species toxicokinetic adjustment factor. Tmax values for steviol were at ∼8 and ∼20 h after administration in rats and humans, respectively. Peak concentrations of steviol were similar in rats and humans, while steviol glucuronide concentrations were significantly higher in humans. Glucuronidation in rats was not saturated over the dose range 40–1000 mg/kg bw. The AUC0-last for steviol was approximately 2.8-fold greater in humans compared to rats. Chemical-specific adjustment factors for extrapolating toxicokinetics from rat to human of 1 and 2.8 were established based on Cmax and AUC0-last data respectively. Because these factors are lower than the default value of 4.0, a higher ADI for steviol glycosides of between 6 and 16 mg/kg bw/d is justified.

Drinking Water: NAS Reports on Perchlorate Safety

A National Academy of Sciences (NAS) panel has issued a final report on the health implications of perchlorate ingestion, recommending a reference dose of 0.0007 milligrams per kilogram (mg/kg) body weight. But the debate over the health risks posed by the chemical, used by the Department of Defense as a rocket fuel additive, is far from over. Perchlorate compounds have been used since the early 1900s, and environmental perchlorate contamination was first seen in 1985 in wells at California Superfund sites. Since then, perchlorate has been found in 35 states. In May 2004 the U.S. Environmental Protection Agency (EPA) estimated that more than 11 million Americans were drinking water from public supplies containing at least 4 parts per billion (ppb) perchlorate. Scientists agree that perchlorate can interfere with the production of thyroid hormone since it competes for the uptake of iodide by the thyroid gland. But beliefs about what level of exposure constitutes a health risk vary widely. The Council on Water Quality (CWQ), a chemical and aerospace industry group, often cites a drinking water cutoff of 245 ppb. In contrast, California recommends that drinking water contain no more than 6 ppb perchlorate, and Massachusetts recommends that pregnant women and children not consume water with more than 1 ppb perchlorate. The broad disagreement, coupled with the prospect of massive cleanup costs—estimated by some to be in the billions—prompted the government to ask the NAS for guidance. According to panel chair Richard B. Johnston, Jr., associate dean for research development at the University of Colorado School of Medicine in Denver, the 15-member group used as its starting point a September 2002 EHP study headed by Monte A. Greer of Oregon Health & Science University. This study was partially funded by the Perchlorate Study Group, an organization created by the Department of Defense and some of its contractors. The Greer study concluded there was no inhibition of iodide uptake by the thyroid at 0.007 mg/kg body weight. The panel applied a 10-fold uncertainty factor to that figure to derive its own reference dose. “We took what we feel is the most conservative end point,” says Johnston. “It’s way short of any kind of harm.” Five weeks after the NAS made its report public, the EPA responded by adopting the NAS dose level and translating it into a drinking water equivalent level of 24 ppb. But environmental groups have voiced heated disagreement with the NAS findings. Gina Solomon, a senior scientist at the Natural Resources Defense Council, says the report relied too heavily on a study she calls statistically flawed because of the small number of subjects (just 37). “As the effect [of perchlorate ingestion] gets more subtle, the size of the study group needs to be bigger to see if there’s an effect there or not,” she says. Further, she says, the report suffers from tunnel vision: “[The NAS] should have been looking at the big picture on perchlorate, and they didn’t do that. The result was that their final report hinged entirely on one controversial industry study.” Johnston responds that the panel also relied on four other clinical studies as well as several epidemiologic and perchlorate worker studies, all of which supported the Greer findings. And James Strock, a former secretary of the California Environmental Protection Agency who now works with the CWQ, says the NAS findings will provide state and federal regulators “a rare opportunity to promulgate regulations in a transparent manner, working simultaneously from information collected and considered by a world-class panel of experts.” Johnston agrees, however, that more research will be helpful, especially on perchlorate’s effects on sensitive populations, such as pregnant women, nursing mothers, and infants. A study at Texas Tech University, published 1 April 2005 in Environmental Science & Technology, found that perchlorate levels in 36 samples of breast milk from nursing mothers in 18 states averaged 10.5 ppb, meaning the mothers were ingesting far more than 24 ppb. The study raises the possibility that some infants may be ingesting perchlorate at levels exceeding NAS and EPA safe doses. Meanwhile, the controversy continues to play out, as described in an upcoming EHP commentary (doi:10.1289/ehp.8254, scheduled for publication in September 2005 and available in draft form at http://dx.doi.org/). Although the EPA has adopted the 24 ppb figure as an “official reference dose,” it’s not yet an enforceable standard, and Solomon says states are left to their own devices. “Some are following the EPA lead, and others are following the California lead,” she says. “This means that consumers in some states will be drinking water with higher levels of perchlorate than consumers in other states. And that’s unfortunate.”

47 Risk characterization

The acceptable daily intake (ADI) of commercially available steviol glycosides is currently 0–4 mg/kg body weight (bw)/day, based on application of a 100-fold uncertainty factor to a no-observed-adverse-effect-level value from a chronic rat study. Within the 100-fold uncertainty factor is a 10-fold uncertainty factor to account for inter-species differences in toxicokinetics (4-fold) and toxicodynamics (2.5-fold). Single dose pharmacokinetics of stevioside were studied in rats (40 and 1000 mg/kg bw) and in male human subjects (40 mg/kg bw) to generate a chemical-specific, inter-species toxicokinetic adjustment factor. Tmax values for steviol were at ∼8 and ∼20 h after administration in rats and humans, respectively. Peak concentrations of steviol were similar in rats and humans, while steviol glucuronide concentrations were significantly higher in humans. Glucuronidation in rats was not saturated over the dose range 40–1000 mg/kg bw. The AUC0-last for steviol was approximately 2.8-fold greater in humans compared to rats. Chemical-specific adjustment factors for extrapolating toxicokinetics from rat to human of 1 and 2.8 were established based on Cmax and AUC0-last data respectively. Because these factors are lower than the default value of 4.0, a higher ADI for steviol glycosides of between 6 and 16 mg/kg bw/d is justified.

The effect of the 14-day agricultural restricted entry interval on azinphosmethyl exposures in a group of apple thinners in Washington state

We examined the effect of the 14-day agricultural restricted entry period on absorbed pesticide doses in a group of twenty experienced apple thinners. Thinners entered orchards 1–49 days following azinphosmethyl applications. Urine samples ( n=296) collected throughout the thinning season were analyzed for the three dialkylphosphate metabolites of azinphosmethyl to estimate absorbed daily doses. Separate dose distributions were created for samples collected when the interval was <14 days, or 14 days or more; geometric mean doses for these two categories differed by a factor of two (42 and 19 μg/kg/day, respectively; p<0.0001). Dose estimates were compared to US Environmental Protection Agency and California EPA regulatory guidance values for occupational azinphosmethyl risk. None of the doses exceeded the U.S. EPA NOAEL (560 μg/kg/day), but nearly all had a margin of exposure of less than 100. Addition of a 10-fold uncertainty factor to California EPAs NOAEL produced a guidance value of 75 μg/kg/day. Only 2.4% of the doses exceeded this value for re-entry intervals 14 days or more, while 27% exceeded the value for re-entry intervals <14 days. We conclude that the 14-day restricted entry interval provides an appropriate level of worker health protection under the field conditions studied.

Evaluating the 10X Uncertainty Factor for Children and Elderly with Data-Derived Values for Neuromuscular Blocking Agents

Conventional risk assessment process utilizes a 10-fold uncertainty factor (UF) to extrapolate from the general human population to sensitive subgroups, such as children and elderly. The purpose of this investigation was to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharmacody-namic data are incorporated to characterize human sensitivity. An extensive literature search was conducted on seven neuromuscular blocking agents (mivacurium, atracurium, rocuronium, vecuronium, doxacurium, pancuronium, pipecuronium). Composite factors (kinetics × dynamics) were calculated using the highest data-derived kinetic and dynamic values. For the drugs examined, all of the composite factors for the sensitivity of children were lower than 5. In the elderly, all of the composite factors were lower than 10, and five of seven composite factors were less than 5. From this study, it was concluded that relevant compound-specific kinetic and dynamic data can reduce the uncertainties associated with sensitive subgroups.

Differential Sensitivity of Children and Adults to Chemical Toxicity: II. Risk and Regulation

Animals can be useful predictors of chemical hazards to humans. Growth and development are compressed into a shorter period in animals, which makes interpretation of animal testing inherently more difficult. However, similar events occur in both humans and laboratory animals and testing that covers the full period of animal development can reasonably be considered an appropriate surrogate for human development. Some have proposed an additional 10-fold factor for the extra protection of children when estimating safe exposures. Use of such an additional factor, as required by the Food Quality Protection Act (FQPA), is meant to address the same issues covered by the EPA's database uncertainty factor, UF D, and additional issues related to exposure uncertainty. Thus, when UF D has already been deployed, the EPA modifies its use of the FQPA factor. Based on our analysis, we agree with the EPA. Drawing conclusions about the adequacy of UF H, the uncertainty factor used to account for intrahuman variability, in terms of its ability to protect children on the basis of the modest data available is challenging. However, virtually all studies available suggest that a high percentage of the population, including children, is protected by using a 10-fold uncertainty factor for human variability or by using a 3.16-fold factor each for toxicokinetic and toxicodynamic variability. Based on specific comparisons for newborns, infants, children, adults, and those with severe disease, the population protected is between 60 and 100%, with the studies in larger populations that include sensitive individuals suggesting that the value is closer to 100%.

Intra-Species Extrapolation in Risk Assessment of Different Classes of Antimicrobials

The risk assessment process for non-carcinogens incorporates all available scientific information, including toxicokinetic and toxicodynamic data. A 10-fold uncertainty factor (UF) is most commonly used to account for underlying variability within the human species. The purposes of this investigation are to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharma-codynamic data are incorporated to characterize interindividual variability and whether another UF is needed for the children group. An extensive literature search was conducted on seven antimicrobials in order to incorporate information on kinetics and dynamics to allow extrapolation among susceptible humans. The drugs are cefaclor, cefuroxime, erythromycin, clarithromycin, ampicillin, gentamicin and amikacin. The composite factor was calculated using the highest ratio for appropriate parameters and default subfactor. According to the data, we concluded that when relevant kinetic and dynamic data are available, replacing the default factors with actual data-derived values was possible for the antimicrobials evaluated and that there is no need to add another UF to the children group.

DETERMINATION OF THE REFERENCE DOSE FOR CHLORPYRIFOS: PROCEEDINGS OF AN EXPERT PANEL

Chlorpyrifos is an extensively used organophosphate insecticide with numerous agricultural crop and urban pest control uses. Dow AgroSciences, one of the manufacturers of chlorpyrifos, convened a panel of toxicology and medical experts to consider the available scientific literature (both published papers and unpublished reports from Dow AgroSciences) on chlorpyrifos with respect to determining the acute and chronic toxicological reference doses (RfD) for chlorpyrifos. The most sensitive effect observed in the body of animal and human studies on chlorpyrifos is the inhibition of the various cholinesterases. In animal studies chlorpyrifos is not carcinogenic, teratogenic, or mutagenic. Reproductive toxicity studies indicate some effects on postnatal survival, but these effects were seen at doses higher than maternal toxic dose levels. There are no clinical signs of cholinergic toxicity below 70% inhibition of brain cholinesterase. Cognitive or behavioral defects are not observed until substantial brain cholinesterase inhibition occurs. There are no indications that chlorpyrifos caused delayed neurotoxicity at dose levels below twice the oral LD50. The panel members stated that plasma cholinesterase was an inappropriate endpoint for the RfD. They recommended that brain, erythrocyte cholinesterase depression and clinical signs were appropriate as endpoints for the RfD. Plasma cholinesterase should be used only as an indicator of exposure. After a thorough review of the experimental animal literature, it was determined that the chlorpyrifos repeated-exposure RfD based on application of a 100-fold uncertainty factor on the no observed adverse effects level (NOAEL) for brain cholinesterase inhibition or on a 10-fold uncertainty factor on the NOAEL for erythrocyte cholinesterase inhibition is 0.01 mg/kg/d. Based on the human volunteer studies, which indicate a repeated-dose NOAEL of 0.1 mg/kg/d for erythrocyte cholinesterase inhibition, and then using a 10-fold uncertainty factor, the RfD is again 0.01 mg/kg/d. In this human volunteer study on d 9 (last day) of administration, 1 individual in the 0.1 mg/kg/day dose group was removed from the study due to a "cold" (runny nose, blurred vision, and a feeling of faintness). He was asymptomatic 12 h later. To some degree this diagnosis is supported by the hematology, since lymphocyte counts were reduced and neutrophil counts were increased markedly, indicating a possible inflammatory reaction on d 8 of dosing, clearing by post-treatment d 5. In the absence of any indication of erythrocyte cholinesterase inhibition and with plasma cholinesterase inhibition being greater in two of the four other individuals treated at the same dose level, these signs and symptoms are unlikely to have been induced by cholinesterase inhibition. The panel concluded that the symptoms this individual displayed were not an appropriate endpoint for the RfD. The single exposure reference dose can be based on the human data. No erythrocyte cholinesterase inhibition or clinical signs of toxicity were observed after a single oral dose of 0.5 mg/kg. Utilizing a 10-fold uncertainty factor, the single-dose RfD is 0.05 mg/kg.