Dennis J. Paustenbach

The European Union’s REACH regulation: a review of its history and requirements

In 2006, the European Union (EU) promulgated a monumental regulatory initiative for the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH). To date, several thousand pages of text have been needed to describe the expectations of this regulation. There were numerous reasons for the promulgation of REACH, but, by and large, it is an extension of the global desire to produce fewer industrial chemicals, to understand the possible human and ecological hazards of those that are produced, and to insure that any major threat is anticipated, as well as prevented. Most industry-related groups consider it the most wide-ranging and costly regulatory initiatives related to health risk assessment ever to be promulgated. This review presents a description of REACH that should inform scientists, managers, and others about its objectives and the means to satisfy them. Registration is required for all chemicals manufactured or imported into the EU, unless specifically exempted. Registration is expected to be a collaborative process among companies, which will generate a dossier containing data on physicochemical characteristics, as well as toxicological and ecotoxicological properties. Though the magnitude of the gaps in the data required for registration is uncertain at this point, it is clear that basic toxicology testing will have to be conducted for many chemical substances that have not undergone formal review up to this point. For many chemicals, an examination of hazards and risks arising from the use of these substances will also be required in the form of a chemical safety report (CSR). Beginning with the dual processes of dossier and substance evaluation, the European Chemicals Agency (ECHA), the Member States of the EU, and the European Commission will identify chemicals that may pose unacceptable hazards to human health and/or the environment, and will curtail or restrict their usage. The implementation of REACH will expand and deepen the fields of applied toxicology and exposure assessment by spurring activity and innovation in sampling and analysis, toxicology testing, exposure modeling, alternative toxicity testing, and risk assessment practices.

THE PRACTICE OF EXPOSURE ASSESSMENT: A STATE-OF-THE-ART REVIEW

Each of us encounters hundreds of toxic agents everyday, without exposure and subsequent absorption (uptake) however, there is no risk of injury. Thus, exposure assessment is one of the three legs of the stool (along with toxicity assessment and dose-response assessment) upon which the practice of risk assessment rests. The field of exposure assessment has evolved out of at least 3 other disciplines over the past 50 years, including health physics, industrial hygiene, and epidemiology. Exposure assessments are a necessary component to understanding the hazard posed by exposure to naturally (e.g., aflatoxins in foods, radon in air) and nonnaturally occurring toxicants (e.g., benzene in groundwater, MTBE in air, and food additives). This article presents a thorough review of the field, including a discussion of the terminology used in exposure assessment, a description of how to quantitatively estimate dose for the major sources of exposure (food, water, air, and soil), and many of the best sources of information. In addition, techniques for assessing both variability and uncertainty are presented. Lessons learned over the past twenty years are emphasized. Some example calculations are included, nearly 400 references are cited, and a glossary of terms is provided.

Evaluation of potential transmission of 2,3,7,8-tetrachlorodibenzo-p-dioxin-contaminated incinerator emissions to humans via foods

Interest in the potential sources of human exposure to TCDD (dioxins, TCDD and equivalents, or 2,3,7,8-tetrachlorodibenzo-p-dioxin) via foods has recently shifted from phenoxy herbicides to products of combustion and waste disposal. Proposals to locate municipal waste combustors in rural areas have raised concerns that emissions, which could contain TCDD, could contaminate animal feeds and such human foods as milk, meat, and vegetables. Important factors that can affect the results of an assessment of incinerator emissions include (1) the emission and deposition rates of TCDD from the source, (2) the fractional retention and half-life of fly ash on plants, (3) the environmental half-life of TCDD, (4) the animal feeding and management systems, (5) the bioavailability of TCDD and related compounds, (6) the metabolism and pharmacokinetics of TCDD in farm animals, (7) food consumption levels, (8) the half-life of TCDD in humans, and (9) the model selected to estimate cancer risk. For persons living in the area of highest deposition near an incinerator, a possible uptake of TCDD from foods of animal origin was estimated to be about 10-40 fg/kg.d, which was much greater than the 1-5 fg/kg.d uptake estimated for foods of plant origin. The total uptake of TCDD from foods by the maximally exposed population will usually be about 500- to 1000-fold greater than that due to inhalation. Although milk was assumed to be the most important food pathway in several previous assessments that evaluated the hazards of airborne emissions, we determined that the deposition-forage-cattle-beef pathway was the more important route of exposure. The previous assessments appear to have used inappropriate pharmacokinetic models for TCDD and to have overestimated pasture use for dairy cows. The amount of TCDD accumulated in soil from airborne emissions was found to be less important than the amount deposited in forage, a finding that is the opposite of the usual conclusions drawn for other routes of TCDD introduction into agricultural environments. Based on the assumption and parameters used in this assessment, the potential human health risks due to TCDD emissions from incinerators are insignificant compared to other background sources of TCDD. It would be desirable to measure TCDD in soil and crops around existing facilities to better evaluate this assessment, but it is likely that concentrations would be too low to reliably quantitate.

Is hexavalent chromium carcinogenic via ingestion? A weight-of-evidence review.

Hexavalent chromium [Cr(VI)] is recognized as a human carcinogen via inhalation, based on elevated rates of lung cancer among occupationally exposed workers in certain industries. Cr(VI) is also genotoxic in bacterial and mammalian cell lines. In contrast, scientific panels in the United States and abroad have reviewed the weight of evidence (WOE) and decided that the available data are insufficient to conclude that Cr(VI) is an oral carcinogen. A criterion of 0.2 ppb was established by a California agency for Cr(VI) in drinking water to prevent cancer, however, this criterion was withdrawn in November, 2001. This criterion was remarkably lower than the promulgated California and federal drinking-water standards for total chromium of 50 ppb and 100 ppb, respectively. Both of the promulgated standards are designed to be protective of humans who ingest Cr(VI). This article describes a WOE analysis to examine the likelihood that Cr(VI) in drinking water poses a cancer hazard at the current U.S. drinking-water standard. The results indicate that: (1) From the historical epidemiological studies, there are a few reports of increased rates of digestive system cancer among Cr(VI)-exposed workers, although most are not statistically significant; (2) the preponderance of evidence from recent epidemiological studies of Cr(VI)-exposed workers does not support an increased risk of cancer outside of the respiratory system; (3) studies of four environmentally exposed populations are negative; (4) there is only one lifetime animal feeding study, and the findings from that study are considered to be flawed and inconclusive; and (5) recent kinetics and in vivo genotoxicity data demonstrate that Cr(VI) is reduced to nontoxic Cr(III) in saliva, in the acidic conditions of the stomach, and in blood. In short, at concentrations at least as high as the current U.S. maximum contaminant level (100 ppb), and probably at least an order of magnitude higher, Cr(VI) is reduced to Cr(III) prior to or upon systemic absorption. The weight of scientific evidence supports that Cr(VI) is not carcinogenic in humans via the oral route of exposure at permissible drinking-water concentrations.

A physiological pharmacokinetic description of the tissue distribution and enzyme-inducing properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat

A five-compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the tissue disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Sprague-Dawley rat. This description included blood, liver, fat, muscle/skin, and visceral tissue groups. On the basis of other literature, the liver compartment was modeled to include two TCDD-binding sites, corresponding to a cytosolic receptor and a microsomal binding protein. A pharmacodynamic description was developed in which microsomal enzyme induction, both of arylhydrocarbon hydroxylase activity and of the amount of the microsomal TCDD-binding protein, was linked to fractional occupancy of the cytosolic receptor. This description was then used to analyze previously published data on TCDD disposition. The dissociation constant of the cytosolic Ah receptor (KB1) in vivo was estimated to be 15 pM by fitting enzyme induction data from McConnell et al. (1984). The ratio of liver to fat concentration of TCDD (about 4:1) was found to be primarily determined by the dissociation constant of the microsomal binding protein (7 nM) and the basal and induced concentration of this protein in the liver (25 and 200 nmol/liver, respectively). With these parameter values, the tissue distribution of TCDD in fat and liver, the two primary sites of accumulation, was accurately described following either single or repeated dosing with TCDD in the rat. The pharmacokinetic behavior described by the model was extremely sensitive to binding affinities, and only moderately sensitive to binding capacities in the dose range studied. Induction of microsomal TCDD-binding proteins was necessary in order to account for the differences in disposition at low (0.01 microgram/kg) and high (1.0 microgram/kg) daily doses of TCDD. Since the tumorigenicity of TCDD in rats is believed to be correlated with the biological responses of the Ah-TCDD complex, the present physiological pharmacokinetic description, which contains information on receptor occupancy at various dose levels, provides a plausible mechanistic connection for devising pharmacodynamic models which predict the cancer risk of TCDD in the rat.

Reevaluation of benzene exposure for the pliofilm (Rubberworker) cohort (1936-1976)

The Pliofilm cohort is the most intensely studied group of workers chronically exposed to benzene. Information on this cohort has been the basis for regulations and/or guidelines for occupational and environmental exposure to benzene. Rinsky et al. (1986, 1987) and Crump and Allen (1984) developed different approaches for reconstructing the exposure history of each member of the group. The predicted levels of exposure, combined with the data on the incidence of disease, have been used to estimate benzenes carcinogenic potency. In this paper, recent information from worker interviews and historical records from the National Archives and elsewhere were used to evaluate the accuracy of prior exposure estimates and to develop better ones for the cohort. The following factors were accounted for: (1) uptake of benzene due to short-term, high-level exposure to vapors, (2) uptake due to background concentrations in the manufacturing building, (3) uptake due to contact with the skin, (4) morbidity and mortality data on workers in the Pliofilm process, (5) the installation of industrial hygiene engineering controls, (6) extraordinarily long work weeks during the 1940s, (7) data indicating that airborne concentrations of benzene were underestimated due to inaccurate monitoring devices and the lack of adequate field calibration mated due to inaccurate monitoring devices and the lack of adequate field calibration of these devices, and (8) likely effectiveness of respirators and gloves. Our estimates suggest that Crump and Allen (1984) overestimated the exposure of workers in some job classifications and underestimated others, and that Rinsky et al. (1981, 1986) almost certainly underestimated the exposure of nearly all workers. Airborne concentrations of benzene at the St. Marys facility during the years of its operation were found (on average) to be about half those of the two Akron facilities. Our analysis indicates that short-term, high-level exposure to benzene vapors and dermal exposure significantly increased (by about 25-50%) the total absorbed dose of benzene for some workers. One of the key findings was that, unlike prior analyses, the three facilities probably had significantly different airborne concentrations of benzene, especially during the 1940s and 1950s.

Absorption and elimination of trivalent and hexavalent chromium in humans following ingestion of a bolus dose in drinking water

These studies investigate the magnitude and valence state of chromium absorbed following plausible drinking water exposures to chromium(VI). Four adult male volunteers ingested a single dose of 5 mg Cr (in 0.5 liters deionized water) in three choromium mixtures: (1) Cr(III) chloride (CrCl3), (2) potassium dichromate reduced with orange juice (cr(III)-OJ); and (3) potassium dichromate [Cr(VI)]. Blood and urine chromium levels were followed for 1-3 days prior to and up to 12 days after ingestion. The three mixtures showed quite different pharmacokinetic patterns. CrCl3 was poorly absorbed (estimated 0.13% bioavailability) and rapidly eliminated in urine (excretion half-life, approximately 10 hr), whereas Cr(III)-OJ was absorbed more efficiently (0.60% bioavailability) but more slowly (half-life, approximately 17 hr), and Cr(VI) had the highest bioavailability (6.9%) and the longest half-life (approximately 39 hr). All three chromium mixtures caused temporary elevations in red blood cell (RBC) and plasma chromium concentrations, but the magnitude and duration of elevation showed a clear trend (Cr(VI) > Cr(III)-OJ > CrCl3). The data suggest that nearly all the ingested Cr(VI) was reduced to Cr(III) before entering the bloodstream based on comparison to RBC and plasma chromium patterns in animals exposed to high doses of Cr(VI). These findings support our prior work which suggests that water-soluble organic complexes of Cr(III) formed during the reduction of Cr(VI) in vivo explain the patterns of blood uptake and urinary excretion in humans at drinking water concentrations of 10 mg/liter or less.

A physiologically based pharmacokinetic model for inhaled carbon tetrachloride

D.J. Paustenbach et al. (1986, Fundam. Appl. Toxicol. 6, 484-497) have described the pharmacokinetics of inhaled, radiolabeled carbon tetrachloride (14CCl4) in male Sprague-Dawley rats exposed for 8 or 11.5 hr/day for 1- or 2-week periods. These studies provided time-course information for exhaled 14CCl4, the exhaled 14CO2 metabolite, and 14C radioactivity eliminated in the feces and urine. A physiologically based pharmacokinetic (PB-PK) model which incorporated partition characteristics of CCl4 (blood:air and tissue:blood partition coefficients), anatomical and physiological parameters of the test species (body weight, organ weights, ventilation rates, blood flows, etc.), and biochemical constants (Vmax and Km) for CCl4 metabolism was developed to describe these results. The PB-PK model accurately predicted the behavior of CCl4 and its metabolites, both the exhaled CCl4 and 14CO2 and the elimination of radioactivity in urine and feces. The metabolism of CCl4, determined by gas uptake studies, was adequately described by a single saturable pathway. Metabolites were partitioned in the model to three compartments; the amounts to be excreted in the breath (as 14CO2), urine, and feces. Of total CCl4 metabolism, 6.5, 9.5, and 84.0% were formed via the degradative pathways leading to CO2, urinary, and fecal metabolites, respectively. The simplest kinetic explanation of the metabolite time course is that 4% of the initially metabolized CCl4 is directly converted to CO2 (probably via a chloroform intermediate) and the remainder of metabolized CCl4 binds to biological substrates. These adducts appear to be slowly degraded with an average half-life of 24 hr. The breakdown products subsequently appear in the feces and urine (the rate constant for elimination by these two routes is similar) and a small portion is converted all the way to CO2. The PB-PK model successfully described the elimination by all four routes for all four exposure scenarios using a single set of parameters. Vmax and Km were, respectively, 0.65 mg/kg/hr and 0.25 mg/liter. There was no evidence for loss of Vmax with repeated exposure, as would be expected if there was enzyme destruction at these concentrations of CCl4. The model was scaled-up to predict the expected behavior of parent CCl4 in monkeys and humans and the resulting simulations compared very favorably with data collected by McCollister et al. (1951) and Stewart et al. (1961). On the basis of this model and the published data on the rat at 100 ppm about 60% of the inhaled CCl4 is metabolized and the resulting blood levels are already in excess of saturation for the metabolizing enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

The Critical Role of House Dust in Understanding the Hazards Posed by Contaminated Soils

The health risks posed by soil pollutants are generally thought to be due to soilingestion and have often resulted in massive regulatory efforts to remedy such contamination. The contribution of this route to the actual human health hazard has been questioned, however, as soil removal alone seems to have little influence on the body burdens of soil contaminants in exposed individuals. Ongoing research also has repeatedly and substantially reduced the estimates of soilingested daily. Because comparatively little time is spent outdoors by most individuals, exposure to soil brought indoors, present as house dust, is now thought to be nearly as important as the directingestion of soil. Exposure via house dust has not been studied specifically, but several observations suggest that it may be important. Dust is largely composed of fine particles of tracked-in soil. The smaller dust particles cling to surfaces better than soil, and contaminant concentrations are often higher in house dust. Fine particles are likely to be more bioavailable, and degradation is slower indoors. Contaminants thus may be concentrated and more readily available in the areas most frequented. In some studies, contaminant levels in dust are correlated more closely with body burdens of contaminants than other sources, suggesting that this route should be considered when assessing risks from soil. Until more research addressing exposure to dust is conducted, recommendations for assessing potential health risks from this pathway are provided.

Biomonitoring and Biomarkers: Exposure Assessment Will Never Be the Same

Using modern analytical technology, it is now possible to measure almost any chemical present in our bodies. The future role of classical exposure assessment will perhaps be marginalized because biomonitoring programs can directly measure the concentration of chemicals that are present in biologic matrices. Although the concentration of chemicals in the environment will continue to be measured and related to exposure parameters, the prioritization of the national environmental agenda will be dictated by biomonitoring. Recent biomonitoring studies have examined the levels of > 200 chemicals. Biomonitoring data, by themselves, are not informative in helping consumers understand their individual health risk. A major challenge facing those who conduct biomonitoring programs is how to best communicate the information to the public. In this article, we review benefits and challenges, along with select results from the Centers for Disease Control and Prevention’s 2005 National Report on Human Exposure to Environmental Chemicals. We recommend that these data be carefully interpreted, with the goal of establishing baseline exposure information, rather than creating surrogates for conclusions about human health risk.