Abdelrazak M. Kadry

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.

Pharmacokinetics of acrylamide after oral administration in male rats

Acrylamide (AMD) is a commonly used industrial chemical. However, it produces a dying back type of peripheral neuropathy in animals and man. This study was performed to investigate the pharmacokinetics of AMD after oral administration at 50 mg/g ([1-(14)C]AMD) in male Sprague-Dawley rats. Absorption from the gastrointestinal tract was rapid and radioactivity was detected in blood 5 min post-administration. The peak plasma concentration occurred 38 min after administration and was equivalent to 47 μg/ml. The elimination pattern for plasma was fitted to a one-compartment model with 6 h half-life. However, in the blood the elimination pattern was fitted to a two-compartment model with 7.93 and 374 h for distribution and elimination phases, respectively. Tissue concentrations of radioactivity determined at 28 and 144 h post-administration differed substantially. After 28 h the highest activity was in the gastric content, followed by stomach, lung, bone marrow and skin, while after 144 h the order of total radioactivity was lung>bone marrow>esophagus. The activities in the rest of the organs in both experiments were very low. The excretion study revealed that the kidney is the major route of elimination and the majority of radioactivity in urine was excreted during the first 12 h. The feces contained approximately 10% of the administered dose after 144 h. This study indicated that AMD is rapidly absorbed from the rats gastrointestinal tract, distributed and eliminated from the body. AMD bound but did not accumulate in the erythrocytes or the neural tissues.

Studies on the use of uncertainty factors in deriving RfDs

Abstract Risk assessment of exposure to chemicals having a toxic end point routinely uses the reference dose (RfD) approach based on uncertainty factors of 10. RfD model can be used with widely different databases. However, the quality of individual risk assessment is unequal among chemicals, often resulting in either an over‐ or underestimation of adverse health risk. The purpose of this investigation was to evaluate whether the magnitude of the 10X uncertainty factors has scientific merit against data from recent human and animal experimental studies. Although we assessed the use of uncertainty factors for representative chemicals from various classes of compounds, such as volatile organics, alcohols, gasoline components, and pesticides, we are presenting our findings for 24 chemicals. A compilation and comparison of ratios between LOAEL/NOAEL (Lowest Observed Adverse Effect Level/No Observed Adverse Effect Level), and subchronic/chronic values were made. Although a 10X uncertainty factor is most common...

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.

Soil adsorption alters kinetics and bioavailability of trichloroethylene in orally exposed female rats

Soil contamination with dangerous toxic chemicals remains one of the most difficult problems in this era. Bioavailability of a chemical absorbed through gastrointestinal tract exposure from contaminated soil may differ from that seen following exposure to the pure chemical. In this study 4.6 microCi of 14C-TCE (trichloroethylene) alone, or adsorbed to clay or sandy soil, was administered to female Sprague-Dawley rats. Maximum plasma levels of radioactivity were highest in the presence of clay soil. However, they were similar for TCE alone and sandy-soil-adsorbed chemical. The half-life (t1/2) of absorption was statistically longer and the half-life of elimination was statistically shorter in the presence of sandy soil compared with TCE alone. There were no differences in the area under the plasma concentration-time curves between groups. Liver and kidney exhibited the highest tissue concentrations of radioactivity in all groups. Urine was the primary route of excretion followed by expired air in the pure- and clay-soil-adsorbed groups. However, equal amounts of the dose were excreted in both urine and expired air of the sandy-soil-adsorbed group with a significant increase of radioactivity in expired air throughout the 72-h study period. Trichloroethanol was the major urinary metabolite of TCE.

Kinetic and dynamic data of analgesics and NSAIDs drugs reduce 10X uncertainty factors

Abstract The risk assessment process must use all available toxicological data and scientific evidence on the adverse effects of chemicals or drugs. The relationship between biological indicators and exposure or tissue burdens is determined by the pharmacokinetic and pharmacodynamic behavior of the chemical. The purpose of the present project was to investigate the use of pharmacokinetic and pharmacodynamic data in reducing the uncertainties in establishing exposure levels for some analgesics and non‐steroidal anti‐ inflammatory drugs (NSAIDs). Five pharmaceuticals were evaluated, namely: naproxen, acetaminophen, aspirin, ibuprofen and ketoprofen. The pharmacokinetic and pharmacodynamic parameters in inter‐ and intra‐species were evaluated. The composite factors for all the examined drugs were far less than 100. The present study indicated that the formation of data basis for different chemicals based on pharmacokinetic and pharmacodynamic behavior is important in setting up exposure levels, rather than t...

A review of the use of uncertainty factors in the health risk assessment of some metals

Abstract Because metals can produce health risks, standards for regulating metal exposure are necessary. The purpose of this chapter is to review the application of uncertainty factors to mercury, arsenic, and cadmium. By the conventional method, uncertainty factors are often applied to animal studies to establish the reference dose (RfD) in humans. However, with the availability of a better database from improved study designs, it was demonstrated that uncertainty factors can be decreased. Incorporation of more pharmacokinetic and mechanistic data into the risk assessment process, as well as discussions between risk assessors and the research community to identify research needs are essential in reducing uncertainty factors.

Inter- and Intra-Species Extrapolation in Risk Assessment of Different Classes of Pesticides

Risk assessors routinely use the reference dose (RfD) approach for non-cancer risk assessment. In this approach, No-Observed-Adverse-Effect-Level (NOAEL) is divided by the product of uncertainty factors (UFs) and, occasionally, an additional modifying factor (MF), each usually employed by default as factors of 10. In the present investigation, kinetic and dynamic data have been used in order to reduce uncertainties when establishing exposure guidelines for examples of chemicals representing four classes of pesticides (warfarin, lindane, carbaryl and parathion). An intensive search of databases was conducted for these pesticides, and toxicokinetic and toxicodynamic parameters in inter- and intra-species were evaluated. The kinetic and dynamic subfactors were less than the proposed values of Renwick and the International Programme on Chemical Safety (IPCS). The composite factors for all the examined pesticides were less than 100. The present study indicated that in setting exposure levels it is important to...