Gloria A. Skowronski

Evaluation of the use of uncertainty factors in deriving RfDs for some chlorinated compounds.

Risk assessment of exposure to chemicals having a toxic endpoint routinely uses the reference dose (RfD) approach based on uncertainty factors of 10. The purpose of this investigation was to evaluate whether the magnitude of the U.S. Environmental Protection Agency (EPA) 10x uncertainty factors has scientific merit when compared with data from recent human and animal experimental studies. A compilation and comparison of ratios between LOAEL/NOAEL (lowest observed adverse effect level/no observed adverse effect level) and subchronic/chronic values was made for six chlorinated compounds, namely, carbon tetrachloride, methylene chloride, pentachlorophenol, monochlorobenzene, chlorpyrifos, and 1,1-dichloroethane. Data sets demonstrated that 91.3% of the LOAEL/NOAEL ratios were < or = 6 while 87% of the ratios for the same parameter were < or = 5. Furthermore, subchronic/chronic ratios were < or = 3.5. From our investigation we concluded that automatic safety factors of 10x are not scientifically supportable and are overly conservative for the chlorinated compounds studied here.

Effects of soil on the dermal bioavailability of m-Xylene in male rats

Bioavailability of a chemical absorbed through the skin from contaminated soil may differ from that seen following exposure to the pure chemical. The objective of this research was to qualitatively and quantitatively assess the absorption, distribution, excretion, and metabolism of soil-adsorbed m-xylene versus pure m-xylene so that the potential for public health risk following dermal exposure could be evaluated. In this study a shallow glass cap covering a 13-cm2 area was fixed to the shaved skin of each male rat (6-10 rats per group) followed by the addition of 225 microliters of m-xylene containing 20 muCi of m-[14C]xylene alone or with one of two soils. Maximum plasma levels of radioactivity were highest for pure m-xylene while the values for the sandy and clay soil groups were approximately equal. Although clay soil statistically decreased the rate of absorption, the half-lives of elimination and the area under the plasma concentration time curve were not changed by either soil. The major route of excretion in the pure and sandy groups was via expired air followed by urine. However, in the presence of clay soil, the percentage of the initial dose in expired air was similar to that in urine. Forty-eight hours after treatment, skin application sites in both soil treatment groups contained amounts of radioactivity significantly higher than those of m-xylene treatment alone. In the presence of clay soil a statistical increase in m-xylene-derived radioactivity was also observed in fat beneath the treated skin area. Metabolite analysis by HPLC indicated that methylhippuric acid was the main urinary metabolite followed by xylenol and the parent compound in all groups.

Soil Adsorption Alters Bioavailability of Benzene in Dermally Exposed Male Rats

The potential for exposure to chemically contaminated soil is a concern for chemical industry and waste disposal site workers as well as for individuals living near the contamination site. Current assessment of potential health risks from these types of exposures relies almost exclusively on extrapolations from data derived with pure chemicals. Complex interactions with soil, however, may alter greatly the way in which a chemical subsequently interacts with the body. This study was conducted to determine if soil adsorption alters the way in which benzene, a common chemical contaminant, enters and is handled by the body following dermal exposure. A shallow glass cap covering approximately a 13-cm2 area was fixed tightly to the shaved skin of each adult male rat tested; 300 microL of 14C-benzene alone or with 1 g of clay or sandy soil was introduced under the cap through an opening which was sealed immediately. Pure benzene produced the highest peak plasma concentration of radioactivity, followed closely by sandy soil-adsorbed benzene, with the lowest value exhibited by clay soil-adsorbed benzene. The plasma elimination half-lives were as follows:sandy (24.5 hr), pure (23.0 hr), and clay (19.4 hr). The tissue concentrations of radioactivity 48 hr post administration were highest in treated skin (covered by the glass cap), followed by the kidney and liver in both soil-treated groups, and were highest in the kidney followed by the liver and treated skin in the pure group.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of the Dermal Bioavailability of Soil-Aged Benzo(a)pyrene

Exposure to polycyclic aromatic hydrocarbons (PAHs) in soil is a major health concern because of their mutagenic and carcinogenic properties. The aim of this research was to determine the dermal bioavailability of benzo(a)pyrene (BaP) aged in either a sandy or a clay soil in order to assess the health risks and remediation goals for the chemical. In vitro flow-through diffusion cell studies were conducted utilizing dermatomed male pig skin. The amount of radioactive chemical was measured that penetrated skin into receptor fluid and which was bound to skin following soap and water decontamination. BaP bioavailability was decreased by 95 to 98% after 3 months of aging in soil relative to the pure compound. Less than 0.3% of the dose was detected in receptor fluid for all treatments. While most of the dose was bound to skin after administering the pure compound, the majority of the radioactivity was found in the soil and decontaminate after aging. The results indicate that the health risk from exposure to BaP is significantly reduced as the compound ages in soil and that less soil cleanup would be needed at sites contaminated with aged BaP.

Soil adsorption alters kinetics and bioavailability of benzene in orally exposed male rats

A study comparing the bioavailability of pure vs soil-adsorbed benzene was conducted in adult, male rats. Animals were gavaged with an aqueous suspension of benzene alone or adsorbed to either a Keyport series (clay soil) or a Cohansey aquifer solid (sandy soil) from New Jersey. Peak plasma concentration of radioactivity was increased in the presence of either soil vs benzene alone while the sandy soil also decreased the time to reach peak vs benzene alone. Either soil produced an increase in the area under the plasma radioactivity-time curve versus benzene alone, while the clay soil did so in a statistically significant manner. The half-life (t1/2) of absorption into plasma was not statistically different in the presence of either soil, while each soil decreased the t1/2 of elimination vs benzene alone and clay soil did so in a statistically significant manner.Two hr after exposure, stomach tissue contained the highest amount of radioactivity followed by fat in all treatment groups. No differences were detected in the tissue concentration of radioactivity between the treatment groups.Expired air was the primary excretion route following exposure to benzene alone with lesser amounts of radioactivity eliminated in the urine during the 48 hr following exposure. The opposite pattern was detected in the presence of clay soil, while expired air and urine represented approximately equal routes of excretion in the presence of sandy soil. Unmetabolized benzene represented the bulk of total radioactivity in the expired air of all treatment groups with [14C]O2 comprising the remainder. Less than 2% of radioactivity was eliminated by the fecal route for all treatments with significantly higher amounts in the clay soil treatment versus benzene alone.Phenol was the primary benzene metabolite detected in the 0–12 hr urines of all treatment groups. Lesser amounts of hydroquinone, catechol, and benzenetriol were also detected. No differences in the metabolite percentages were detected between the treatment groups.

ORAL BIOACCESSIBILITY OF TRIVALENT AND HEXAVALENT CHROMIUM IN SOIL BY SIMULATED GASTRIC FLUID

Chromium is found in soil from natural sources and anthropogenic activities. The ingestion of soil contaminated with chromium especially by children can have toxic consequences. Therefore, it is important to quantify the oral bioaccessibility of chromium in contaminated soil. In this study, chromium-51 as chromic(III) chloride and sodium chromate(VI), was mixed with an Atsion sandy soil and a Keyport clay soil and stored for 4 mo at either 21-25°C or 2-4°C. Utilizing simulated gastric conditions, the oral bioaccessibility of chromium in soil was determined. When the effects of soil on the bioaccessibility of chromium were compared, the data revealed that the bioaccessibility of chromium(III) from the clay soil was significantly lower than from the sandy soil at 21-25°C. However, at 2-4°C, more chromium(III) was extracted by synthetic gastric fluid from the clay soil than from the sandy soil. Temperature was also a factor as evidenced by the higher bioaccessibility of chromium(VI) in the sandy soil at 2-4°C and of both chromium species in the clay soil at the same temperature. Reduction of the soluble chromium(VI) chemical to the nonsoluble chromium(III) compound in the acidic soils by naturally occurring organic matter in soil would explain the lower bioaccessibility of chromium(VI) at 21-25°C. At 2-4°C, the data indicate that the rate of chromium(VI) reduction to chromium(III) was slowed. Although the results of this study are limited to one low concentration of chromium(III) and chromium(VI) and indicate that the bioaccessibility of chromium in soil can range between 18% and 72%, the data also suggest that there may be a potential health hazard from oral exposure to chromium in heavily contaminated sites. Therefore, more extensive research should be conducted to determine if these findings can be extended to environmentally relevant concentrations.

Relevance of the 10X Uncertainty Factor to the Risk Assessment of Drugs Used by Children and Geriatrics

Conventional risk assessment practices utilize a tenfold uncertainty factor (UF) to extrapolate from the general human population to sensitive subgroups, such as children and geriatrics. This study evaluated whether the tenfold UF can be reduced when pharmacokinetic and pharmacodynamic data for pharmaceuticals used by children and geriatrics are incorporated into the risk assessment for human sensitivity. Composite factors (kinetics X dynamics) were calculated from data-derived values for bumetanide, furosemide, metoprolol, atenolol, naproxen, and ibuprofen. For the compounds examined, all of the composite factors were lower than 10. Furthermore, 8 of the 12 composite factors were less than 5.5. Incorporation of human kinetic and dynamic data into risk assessment can aid in reducing the uncertainties associated with sensitive subgroups and further study is encouraged.

Effect of a chemical mixture on dermal penetration of arsenic and nickel in male pig in vitro

Abstract The effect of a chemical mixture on the dermal penetration of arsenic or nickel was assessed by applying arsenic-73 or nickel-63 alone or with the chemical mixture to dermatomed male pig skin samples in flow-through diffusion cells. The chemical mixture consisted of chloroform, phenanthrene, and toluene for arsenic penetration studies and phenol, toluene, and trichloroethylene (TCE) for nickel studies. These are predominant chemicals found at hazardous waste sites. Arsenic and nickel bind to skin after dermal exposure. Total penetration of arsenic and nickel in the chemical mixture were significantly increased by 33% and 20% compared to arsenic and nickel alone, respectively. While more radioactivity penetrated skin with chemical treatment than metal alone, significantly less radioactivity was loosely adsorbed to skin and could be easily washed off from the skin surface with soap and water. The results of this study indicate that the potential health risk from dermal exposure to arsenic or nickel is enhanced if other chemicals are present.

Soil decreases the dermal penetration of phenol in male pig in vitro.

Skin is a primary route of exposure to phenol, a major chemical found in hazardous waste sites. The effect of soil adsorption on the dermal bioavailability of phenol was assessed by applying [14C]phenol alone (P) or with sandy (P-S) or clay (P-C) soil to dermatomed male pig skin samples in flow-through diffusion cells. Maximum penetration of P-S and P-C was significantly decreased by one-half and by two-thirds, respectively, compared to P. Furthermore, the penetration of phenol into receptor fluid and the amount bound to skin were significantly lower when phenol was adsorbed to either soil versus P. While less radioactivity penetrated skin with soil-adsorbed phenol treatment than P, significantly more radioactivity was loosely adsorbed to skin and could be easily washed off of the skin surface by soap and water. Only a small fraction (< 5%) of the chemical was metabolized by skin to hydroquinone and catechol in all treatment groups. The results of this study indicate that the bioavailability and thus the potential health risk from dermal exposure to phenol is reduced if the chemical is adsorbed to soil.

Effects of soil on percutaneous absorption of toluene in male rats

Previous assessments of health risks from soil-adsorbed chemical exposures relied on extrapolations from data derived with pure compounds. However, interactions between chemical and soil can alter the rate, amount, and form of chemical that enters the body, resulting in effects that are different from those that occur after exposures to chemical alone. In this study, male rats were treated dermally with [14C]toluene alone or adsorbed to either a sandy or a clay soil. Both soils produced a higher plasma concentration compared to pure toluene, with a statistical decrease in half-life of absorption observed after sandy soil-adsorbed treatment. The time to reach peak plasma concentration, half-life of elimination, and area under the plasma concentration-time curve (AUC) were similar for all groups. Skin and fat contained the highest concentration of radioactivity 48 h after all treatments. Pure and soil-adsorbed toluene were primarily metabolized and excreted via the kidney rather than exhaled. Furthermore, soil treatment did not alter the percentages of the metabolic products.