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

Abstract

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.

Interspecies comparison of kinetic data of chlorinated chemicals of potential relevance to risk assessment

“…As with other organophosphate compounds, the principal mechanism of action for chlorpyrifos is inhibition of acetylcholinesterase in mice, rats, dogs, and humans (McCollister, et al, 1974;Deacon et al, 1980;Nolan et al, 1984a;Young, Szabo, and Grandjean, 1990). It is also interesting that for oral chronic exposure to chlorpyrifos, the NOAEL ratio (for acetylcholinesterase inhibition) between animals and humans was 3.3 and 1 when rat and dog data were used, respectively, and not the default of 10 (Kadry, Skowronski, and Abdel-Rahman, 1995). The chronic NOAEL for mice was not available.…”

Overview: Uncertainty in noncancer risk assessment

“…Several reports describe the underlying scientific basis of uncertainty factors (Zielhuis and van der Kreek, 1979;Dourson and Stara, 1983). Research has also been conducted in this area (see, for example, Calabrese, 1985;Hattis, Erdreich, and Ballew, 1987;Renwick, 1991Renwick, , 1993Dourson, Knauf, and Swartout, 1992;Calabrese, Beck, and Chappell, 1992;Lewis, 1993;Calabrese and Gilbert, 1993;Kadry, Skowronski, and Abdel-Rahman, 1995). The following reports of the workshop enhance this existing research.…”

The Application of Non-Default Uncertainty Factors in the U.S. EPA's Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other Uncertainty Factors”

“…They also assumed that the underlying processes that contribute to population variability were multiplicative and that the median value of the distribution would be 3.2. Kadry et al (65) compared the LOAEL/NOAEL ratios for six chlorinated compounds and reported that 91.3% were less than or equal to 6. Similarly, Alexeef et al (66) found that the 95th percentile of the distribution of the LOAEL/NOAEL ratio was 6.3 for extrapolating from an acute inhalation LOAEL to a NOAEL for mild effects.…”