Paul K. Scott

Perinatal Exposure to Low Doses of Dioxin Can Permanently Impair Human Semen Quality

Background In recent decades, young men in some industrialized areas have reportedly experienced a decrease in semen quality. Objective We examined effects of perinatal dioxin exposure on sperm quality and reproductive hormones. Methods We investigated sperm quality and hormone concentrations in 39 sons (mean age, 22.5 years) born between 1977 and 1984 to mothers exposed to dioxin after the accident in Seveso, Italy (1976), and 58 comparisons (mean age, 24.6 years) born to mothers exposed only to background dioxin. Maternal dioxin levels at conception were extrapolated from the concentrations measured in 1976 serum samples. Results The 21 breast-fed sons whose exposed mothers had a median serum dioxin concentration as low as 19 ppt at conception had lower sperm concentration (36.3 vs. 86.3 million/mL; p = 0.002), total count (116.9 vs. 231.1; p = 0.02), progressive motility (35.8 vs. 44.2%; p = 0.03), and total motile count (38.7 vs. 98 million; p = 0.01) than did the 36 breast-fed comparisons. The 18 formula-fed exposed and the 22 formula-fed and 36 breast-fed comparisons (maternal dioxin background 10 ppt at conception) had no sperm-related differences. Follicle-stimulating hormone was higher in the breast-fed exposed group than in the breast-fed comparisons (4.1 vs. 2.63 IU/L; p = 0.03) or the formula-fed exposed (4.1 vs. 2.6 IU/L; p = 0.04), and inhibin B was lower (breast-fed exposed group, 70.2; breast-fed comparisons, 101.8 pg/mL, p = 0.01; formula-fed exposed, 99.9 pg/mL, p = 0.02). Conclusions In utero and lactational exposure of children to relatively low dioxin doses can permanently reduce sperm quality.

Age- and Concentration-Dependent Elimination Half-Life of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Seveso Children

Objective Pharmacokinetic and statistical analyses are reported to elucidate key variables affecting 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elimination in children and adolescents. Design We used blood concentrations to calculate TCDD elimination half-life. Variables examined by statistical analysis include age, latency from exposure, sex, TCDD concentration and quantity in the body, severity of chloracne response, body mass index, and body fat mass. Participants Blood was collected from 1976 to 1993 from residents of Seveso, Italy, who were < 18 years of age at the time of a nearby trichlorophenol reactor explosion in July 1976. Results TCDD half-life in persons < 18 years of age averaged 1.6 years while those ≥18 years of age averaged 3.2 years. Half-life is strongly associated with age, showing a cohort average increase of 0.12 year half-life per year of age or time since exposure. A significant concentration-dependency is also identified, showing shorter half-lives for TCDD concentrations > 400 ppt for children < 12 years of age and 700 ppt when including adults. Moderate correlations are also observed between half-life and body mass index, body fat mass, TCDD mass, and chloracne response. Conclusions Children and adolescents have shorter TCDD half-lives and a slower rate of increase in half-life than adults, and this effect is augmented at higher body burdens. Relevance Modeling of TCDD blood concentrations or body burden in humans should take into account the markedly shorter elimination half-life observed in children and adolescents and concentration-dependent effects observed in persons > 400–700 ppt.

A Methodology for Estimating Human Exposure to Perfluorooctanoic Acid (PFOA): A Retrospective Exposure Assessment of a Community (1951–2003)

Perfluorooctanoic acid (PFOA) is a persistent chemical that was recently shown to be widely distributed in the ambient environment. Because of concerns about the possible adverse health effects on persons exposed to PFOA, a retrospective exposure assessment was conducted for a population of about 50,000 persons who reside near one of the facilities where this chemical was used. No similar study of any chemical with the properties of PFOA had ever been performed; thus, several novel methods were developed and applied in this analysis. Historical records of the emissions from the facility were the basis for the estimates of the potential intake of (PFOA) by residents over the past 53 yr. Various well-accepted environmental models were dynamically combined in order to estimate the concentrations in all relevant environmental media including ambient air, surface soil, drinking water, and homegrown vegetables. Following considerable analyses, particulate deposition from facility air emissions to soil and the subsequent transfer of the chemical through the soil was determined to be the most likely source of PFOA that was detected in groundwater. The highest off-site environmental concentrations were predicted to occur about 1 mile away. For this approximately 1½ square mile area, during the time period 1951–2003, the model-estimated average air concentration was 0.2 μg/m3, the estimated surface soil concentration was 11 μg/kg, and the estimated drinking water concentration was 4 μg/L. Similar data were generated for 20 additional geographical areas around the facility. Comparison of measured PFOA concentrations in groundwater in the various water districts indicated that the models appeared to overpredict recent groundwater concentrations by a factor of 3 to 5. The predicted historical lifetime and average daily estimates of PFOA intake by persons who lived within 5 miles of the plant over the past 50 yr were about 10,000-fold less than the intake of the chemical not considered as a health risk by an independent panel of scientists who recently studied PFOA.

Evaluation of PCDD/F and dioxin-like PCB serum concentration data from the 2001–2002 National Health and Nutrition Examination Survey of the United States population

In 2007, we published a paper in the Journal of Exposure Science and Environmental Epidemiology describing PCDD/F and dioxin-like PCB serum concentration data collected for the 2001–2002 National Health and Nutrition Examination Survey. Since publication of this paper, several of the 1998 World Health Organization Toxic Equivalency Factors (TEFs), which were used to calculate the summary statistics we presented, have been changed. In this addendum, we publish new reference statistics using the WHO2006 TEFs in addition to assessing the effect of these new TEFs on total TEQ concentrations for the general US population. We also examined the effect of the limits of detection (LODs) on the calculated TEQ summary statistics for the top seven contributing congeners and completed a missing data analysis to determine whether our estimates were biased by excluding individuals without complete congener profiles. Similar to our previous results, 2, 3, 7, 8-TCDD; 1, 2, 3, 7, 8-PeCDD; 1, 2, 3, 6, 7, 8-HxCDD; 2, 3, 4, 7, 8-PeCDF; and PCB 126 contributed the most to total TEQ. However, both PCB 156 and 157 were no longer significant contributors, instead being displaced by 1, 2, 3, 4, 7, 8-HxCDF, and PCB 169. In general, the decrease in TEFs for the mono-ortho-substituted PCBs decreased their contribution to total TEQ appreciably, causing TEQ17-9 to approximately equal TEQ17-3. The effect of LODs for five of the top seven contributing congeners was negligible; however, the LODs for 2, 3, 7, 8-TCDD and 1, 2, 3, 7, 8-PeCDD were noticeably higher and may impact TEQ estimates primarily for individuals aged 20–29 years. Results from the missing data analysis provide compelling evidence that the summary statistics we reported previously, as well as those described here, were not greatly influenced due to censoring data.

Identifying soil cleanup criteria for dioxins in urban residential soils: how have 20 years of research and risk assessment experience affected the analysis?

This article reviews the scientific evidence and methodologies that have been used to assess the risks posed by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and presents a probabilistic analysis for identifying virtually safe concentrations of TCDD toxicity equivalents (TEQ) in residential soils. Updated data distributions that consider state-of-the-science cancer and noncancer toxicity criteria, child soil ingestion and dermal uptake, bioavailability in soil, and residential exposure duration are incorporated. The probabilistic analysis shows that the most sensitive determinants of dose and risk are childhood soil ingestion, exposure duration, and the selected TCDD cancer potency factor. It also shows that the cancer risk at 1 per 100,000 predicted more conservative (lower) soil criteria values than did the noncancer hazard (e.g., developmental and reproductive effects). In this analysis, acceptable or tolerable soil dioxin concentrations (TCDD TEQ) ranged from 0.4 to 5.5 ppb at the 95th percentile for cancer potency factors from 9600 to 156,000 (mg/kg/d)−1 with site-specific adjustments not included. Various possible soil guidelines based on cancer and noncancer risks are presented and discussed. In the main, the current toxicology, epidemiology, and exposure assessment data indicate that the historical 1 ppb TEQ soil guidance value remains a reasonable screening value for most residential sites. This analysis provides risk managers with a thorough and transparent methodology, as well as a comprehensive information base, for making informed decisions about selecting soil cleanup values for PCDD/Fs in urban residential settings. This analysis was funded by the Dow Chemical Company, which has been studying PCDD/Fs for more than four decades. The firm has been and is currently involved in litigation related to PCDD/F contaminated soils. Each of the authors has researched the toxicology and risk assessment issues on dioxins for the past 10 to 25 yr and has provided consultations to various industrial, commercial, and governmental clients regarding the underlying science and presented their interpretations in academic, regulatory, and/or litigation settings. Dr. Paustenbach has been and continues to serve as an expert in dioxin litigation involving Dow Chemical Company.

Urinary chromium concentrations in humans following ingestion of safe doses of hexavalent and trivalent chromium : Implications for biomonitoring

In this study, we evaluate the significance of increased urinary chromium concentrations as a marker of chromium exposure and potential health risk. Six human volunteers ingested trivalent chromium [Cr(III)] and hexavalent chromium [Cr(VI)] at doses that are known to be safe but are much higher than typical dietary levels. The following dosing regimen was used: d 1-7, 200 micrograms/d chromium picolinate (a dietary supplement); d 8-10, Cr(VI) ingestion at the U.S. Environmental Protection Agency (EPA) reference dose (RfD) of 0.005 mg/kg/d; d 11-13, no dose; d 14-16, Cr(III) ingestion at the U.S. EPA RfD of 1.0 mg/ kg/d; and d 17-18, postdose. Urine voids were collected throughout the dosing periods and analyzed for chromium. Our findings are as follows: (1) ingestion of 200 micrograms/d of chromium picolinate yielded significantly elevated urine concentrations such that each participant routinely exceeded background, (2) ingestion of the Cr(VI) RfD (0.005 mg/kg/d) yielded individual mean urinary chromium levels (1.2-23 micrograms/L) and a pooled mean urinary chromium level (2.4 micrograms/L) that significantly exceeded background, and (3) ingestion of the Cr(III) RfD yielded no significant increase in urinary chromium concentrations, indicating that little, if any, absorption occurred. Our work identified three critical issues that need to be accounted for in any future studies that will use urinary chromium as a marker of exposure. First, a minimum urinary chromium concentration of approximately 2 micrograms/L should be used as a screening level to critically identify individuals who may have experienced elevated exposures to chromium. Second, if Cr(III) levels in soils are known to be less than 80,000 ppm and the Cr(III) is insoluble, urinary chromium concentrations are not an appropriate marker of exposure. Third, newer forms of chromium supplements that contain organic forms of Cr(III) must be considered potential confounders and their contribution to residential chromium uptake must be carefully evaluated.

The Use of Multizone Models to Estimate an Airborne Chemical Contaminant Generation and Decay Profile: Occupational Exposures of Hairdressers to Vinyl Chloride in Hairspray During the 1960s and 1970s

Vinyl chloride (VC) was used as a propellant in a limited percentage of aerosol hairspray products in the United States from approximately 1967 to 1973. The question has arisen whether occupational exposures of hairdressers to VC-containing hairsprays in hair salons were sufficient to increase the risk for developing hepatic angiosarcoma (HAS). Transient two-zone and steady-state three-zone models were used to estimate the historical airborne concentration of VC for individual hairdressers using hairspray as well as estimated contributions from other hairdressers in the same salon. Concentrations of VC were modeled for small, medium, and large salons, as well as a representative home salon. Model inputs were determined using published literature, and variability in these inputs was also considered using Monte Carlo techniques. The 95th percentile for the daily time-weighted average exposure for small, medium, and large salons, assuming a market-share fraction of VC-containing hairspray use from the Monte Carlo analysis, was about 0.3 ppm, and for the home salon scenario was 0.1 ppm. The 95th percentile value for the cumulative lifetime exposure of the hairdressers was 2.8 ppm-years for the home salon scenario and 2.0 ppm-years for the small, medium, and large salon scenarios. If using the assumption that all hairsprays used in a salon contained VC, the 95th percentile of the theoretical lifetime cumulative dose was estimated to be 52-79 ppm-years. Estimated lifetime doses were all below the threshold dose for HAS of about 300 to 500 ppm-years reported in the published epidemiology literature.

An Adaptable Internal Dose Model for Risk Assessment of Dietary and Soil Dioxin Exposures in Young Children

An adaptable model is presented for assessing the blood lipid concentrations of polychlorodibenzodioxins and polychlorodibenzofurans (PCDD/Fs) from dietary (breast milk, formula, milk, and other foods) and soil pathway exposures (soil ingestion and dermal contact) utilizing age-specific exposure and intake estimates for young children. The approach includes a simple one-compartment (adipose volume) toxicokinetic model that incorporates empirical data on age-dependent half-lives and bioavailability of PCDD/F congeners, child body size and intake rates, and recent data on breast milk and food dioxin levels. Users can enter site-specific soil concentration data on 2,3,7,8-chlorinated PCDD/F congeners for specific assessment of body burden changes from soil pathways in combination with background dietary exposures from birth through age 7 years. The model produces a profile of the estimated PCDD/F concentration in blood lipid (in World Health Organization 1998 dioxin toxic equivalents) versus time for a child from birth through age 7 years. The peak and time-weighted average (TWA) internal dose (defined as blood lipid dioxin toxic equivalents) for a variety of specific child exposure assumptions can then be compared to safe internal dose benchmarks for risk assessment purposes, similar to an approach taken by United States Environmental Protection Agency for assessing child lead exposures. We conclude that this adaptable toxicokinetic model can provide a more comprehensive assessment of potential health risks of PCDD/Fs to children because it integrates recent empirical findings on PCDD/F kinetics in humans and allows users to assess contributions from varied dietary and site-specific environmental exposure assumptions.

Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes

A dose-response relationship between serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and adult diabetes risk has been reported among U.S. Vietnam veterans in the Ranch Hand (RH) cohort. We examine the hypothesis that diabetes progression leads to higher serum dioxin (reverse causation) rather than higher serum dioxin leading to diabetes (causation) across the longitudinal medical monitoring data on these airmen. Lipid-adjusted serum dioxin levels and clinical parameters relating to diabetes progression were examined. Potential confounding due to age, race, diabetes family history, serum total lipid, and body mass index (BMI) was accounted for. The similar incidence of diabetes in RH and Comparison veterans, along with generally similar incidence trends with dioxin decile and lipid decile despite the large differential in serum dioxin, is evidence consistent with reverse causation. Of 135 RH diabetics with at least two dioxin measurements, 32.6% had a temporary serum dioxin increase more than a decade after Vietnam tour and another 22.2% had an interval of unusually slow half-life (>15.5 years); these diabetes-related changes shifted more diabetics into the higher dioxin deciles. Further, the increased diabetes odds ratio among the generally younger RH veterans in the highest dioxin decile is associated with a higher incidence of adult obesity in this RH subgroup, both at tour of duty and decades later. Change in serum dioxin levels is likely due to diabetes progression or poor control and is not independently related to serum dioxin concentrations. In summary, the data from the Ranch Hand studies does not indicate that dioxin increases adult diabetes risk.

Evaluation of bystander exposures to asbestos in occupational settings: A review of the literature and application of a simple eddy diffusion model

This article presents a review of the publicly available information as it relates to airborne asbestos concentrations at varying distances from a source in an occupational environment. Personal and area samples collected 5–75 feet from the primary worker from workplace surveys conducted in the 1970s and area samples collected 5–50 feet from the primary worker during more recent simulation studies were identified, compiled, and analyzed. As expected, airborne asbestos concentrations generally decreased with distance from the worker who performed a given task. Based on this review, however, the authors found that no systematic research to quantitatively relate fiber concentration with distance from the source (including consideration of fiber length, dilution ventilation, and initial momentum of the particle) has been conducted to date. A simple mathematical model was therefore used, and the results were considered, along with available published data comparing exposure data for both workers and persons/areas near workers. From this analysis, the authors offer guidance for estimating airborne asbestos concentrations at distance from a source. Based on the available data and our modeling results, the authors propose the following approach as a rule of thumb: for persons 1–5 feet from the source, airborne asbestos concentrations can be roughly approximated at 50% of the source concentration; 35% at >5–10 feet, 10% for >10–30 feet, and less than 1% at distances greater than 30 feet. This approach should be helpful for bracketing the range of likely exposures to bystanders being evaluated in asbestos-related dose-reconstruction analyses.