Interspecies differences in perfluoroalkyl substances (PFAS) toxicokinetics and application to health-based criteria.

Toxicokinetics are important for extrapolating health effects and effect levels observed in laboratory animals to humans for purposes of establishing health-based criteria. We conducted a comprehensive review of key absorption, distribution, metabolism, and excretion (ADME) parameters across different mammalian species for five perfluoroalkyl substances (PFAS) and discussed how these data can be used to inform human health risk assessment of these substances. Our analysis revealed several notable differences among the different PFAS regarding species- and substance-specific tissue partitioning, half-life, and transfer to developing offspring via the placenta or lactation, as well as highlighted data gaps for certain substances. We incorporated these observations in an analysis of whether health-based values for specific PFAS can be applied to other PFAS of differing chain length or toxicological mode of action. Overall, our analysis provides one of the first syntheses of available empirical PFAS toxicokinetic data to facilitate interpreting human relevance of animal study findings and developing health-based criteria for PFAS from such studies.

Do individuals with asthma experience airway hyper-responsiveness after exposure to nitrogen dioxide?

The current 100 ppb short-term National Ambient Air Quality Standard for NO2, and EPA's determination of a causal association for respiratory effects, are based in part on controlled human exposure studies evaluating airway hyper-responsiveness (AHR). A meta-analysis by Goodman et al. (2009) found increased AHR at 100 ppb NO2 but no clear concentration-response relationship up to 600 ppb, and an overall lack of an AHR effect for studies involving exercise or exposure to allergens. Several factors have been suggested to explain why effects on AHR are observed while people are at rest, but not during exercise or after exposure to allergens. These include an exercise-induced refractory period; partial reversal of bronchospasm from use of forced expiration maneuvers; and greater airway responsiveness of participants exposed to NO2 at rest. We reviewed the scientific evidence to determine whether there is biological support for these factors and found that none sufficiently explained the lack of an effect during exercise or after exposure to allergens. In the absence of either a consistent concentration-response or a plausible explanation for the paradoxical AHR findings, the biological significance of these findings is uncertain and provides equivocal support for NO2 as a causal factor of AHR at these exposure levels.

Do group responses mask the effects of air pollutants on potentially sensitive individuals in controlled human exposure studies?

To establish primary National Ambient Air Quality Standards (NAAQS) for criteria air pollutants such as nitrogen dioxide (NO2), ozone (O3), and sulfur dioxide (SO2), US EPA relies in part on controlled human exposure studies. It has been suggested that evaluating average responses for all participants in these studies may not reflect the responses of sensitive participants in these studies. To evaluate this, we identified controlled exposure studies with multiple exposure concentrations or durations that provided individual-level lung function data. Based on individual lung function responses at specific exposure concentrations and the slope of individual concentration-response curves, we identified 12 participants out of a total of 208 participants in 12 studies who were potentially sensitive to O3, SO2, or sulfuric acid (H2SO4). We did not identify any participants sensitive to NO2. All of these participants were found to be potentially sensitive only at concentrations that were well above the NAAQS (SO2), above likely ambient concentrations (H2SO4), or at concentrations at which the study reported significant lung function effects for all participants (O3). Based on our analysis, average responses for all participants combined adequately reflect lung function responses for potentially sensitive study participants at concentrations in the range of the current NAAQS.

Determining soil remedial action criteria for acute effects: the challenge of copper.

Gastrointestinal (GI) symptoms, the primary acute effect of the essential micronutrient copper, paradoxically occur at lower exposure levels than hepatotoxicity, the primary chronic effect. We developed a remedial action criterion (RAC) for copper to protect against GI symptoms, which primarily relate to the stomach copper concentration, and subside within an hour. Using Monte Carlo methods, we generated a distribution of RACs protective against GI symptoms for a 1 h exposure (hourly RACs) based on soil ingestion rate, volume of liquid and food in the stomach, and bioaccessibility. We then generated a distribution of daily RACs, selected as the minimum hourly RAC for each day over a year, constrained by total daily soil ingestion. Next, we identified a percentile of the distribution of daily RACs, and associated RAC, that would result in a high probability of having a minimal number of GI symptom episodes per year. Our analysis indicates that a copper concentration of 3600 mg/kg would result in a 95% probability of having fewer than five episodes of GI symptoms per year, for a child ingesting outdoor soil 180 days per year. Children residing near copper smelters are most likely to experience GI symptoms from ingestion of copper in soil.

Meta-analysis of nitrogen dioxide exposure and airway hyper-responsiveness in asthmatics.

The effects of 0.1 to 0.6 ppm nitrogen dioxide (NO2) on airway hyper-responsiveness (AHR) to airway challenges in asthmatics have been evaluated in several controlled exposure studies. The authors conducted meta-analyses and meta-regressions of these studies using several effect measures for AHR: a change (in NO2 versus air) in (1) the provocative dose of a challenge agent necessary to cause a specified change in lung function (PD), (2) the change in FEV1 after an airway challenge, and (3) the fraction of subjects with increased AHR. Although several effect estimates from the meta-analyses are statistically significant, they are all so small that they are not likely to be clinically relevant. More importantly, there are no exposure-response associations for any effect estimates based on linear meta-regressions or analyses of effect estimates for exposure groups (0.1 to <0.2 ppm, 0.2 to <0.3 ppm, etc.). This is also generally the case for analyses stratified by airway challenge (specific/nonspecific), exposure method (mouthpiece/whole chamber), and activity during exposure (rest/exercise). The results of these analyses indicate that, to the extent the effects observed are associated with NO2 exposure, they are sufficiently small such that they do not provide evidence that NO2 has a significant adverse effect on AHR at concentrations up to 0.6 ppm.

Effects of six months of daily low-dose perchlorate exposure on thyroid function in healthy volunteers.

CONTEXT: Perchlorate has been detected in U.S. drinking water supplies at levels ranging from 4 to 200 microg/liter as well as in agricultural products. Perchlorate is known to be a competitive inhibitor of iodine uptake by the thyroid through the sodium-iodide symporter. OBJECTIVE: The objective of the study was to determine whether prolonged exposure (6 months) to low levels of perchlorate would perturb thyroid function. DESIGN: This was a prospective, double-blinded, randomized trial. PARTICIPANTS: The study population consisted of 13 healthy volunteers. INTERVENTION: INTERVENTIONs included placebo vs. 0.5 mg or 3.0 mg potassium perchlorate daily. MAIN OUTCOME MEASURES: Serum thyroid function tests, 24-h radioactive iodine uptake, serum thyroglobulin (Tg), urinary iodine and perchlorate, and serum perchlorate were measured. RESULTS: Mean urinary perchlorate value during ingestion of 0.5 mg perchlorate daily was 332.7 +/- 66.1 microg per 24 h or 248.5 +/- 64.5 microg/g creatinine and mean values for the four subjects who received 3 mg perchlorate daily were 2079.5 +/- 430.0 microg per 24 h or 1941.7 +/- 138.5 microg/g creatinine. There was no significant change in the thyroid (123)I uptakes during perchlorate administration. There were no significant changes in serum T(3), free T(4) index, TSH, or Tg concentrations during the exposure period, compared to baseline or postexposure values. Urine iodine values for the 3-mg perchlorate group were higher, but not significantly so, at baseline than during perchlorate exposure. CONCLUSIONS: We observed that a 6-month exposure to perchlorate at doses up to 3 mg/d had no effect on thyroid function, including inhibition of thyroid iodide uptake as well as serum levels of thyroid hormones, TSH, and Tg.