Extrapolation for Exposure Duration in Oral Toxicity: A Quantitative Analysis of Historical Toxicity Data

Guidance on selected default values to be used by the EFSA Scientific Committee, Scientific Panels and Units in the absence of actual measured data

“…It can be noted that the geometric means of the oral subchronic to chronic ratios were similar in all these studies, and approximately equal to 2. Vermeire (1999Vermeire ( , 2001 Used the 70 pairs of NOAELS from Groeneveld (2001) 2 Kalberlah (1998Kalberlah ( , 2003 Unspecified number of pairs of NOAELsrats and mice combined (1998) 35 pairs of NOAELs from NTP studies (2003) 1.7 to 2.9 Groeneveld (1999Groeneveld ( , 2004 56 pairs of NOAELS -rat only from the TNO database 70 pairs of NOAELS -rats and mice from the TNO database 2.3 (2.25 to 2.28) Bitsch (2006) 20 pairs of LOAELs from rats and mice 2 Hasegawa (2010) 33 pairs of NOAELs from rats and mice 68 datasets from public reports or papers 1.7 (2002) Not defined Subchronic to chronic 10 EU (EC, 1996) Industrial chemicals Case-by-case based on expert judgement of scientific information EMEA/ICH (1997) Residual solvents in pharmaceuticals 6-month rodents to chronic 2 3-month rodents to chronic 5 < 3-month rodents to chronic 10 EC (1967) Classification and labelling of chemicals for health effects Subacute to subchronic 3 ECHA (2010) REACH chemicals Subacute to subchronic 3 Subchronic to chronic 2 Subacute to chronic 6 Subacute: 28-day, subchronic: 90-day, chronic: 1.5 -2 years.…”

“…Different methodologies in the literature have provided estimates of distributions of UFs for the inter-/intra-species extrapolation (Hasegawa, 2010;Vermeire et al, 1998 andFalk-Filipsson, 2007), for the exposure duration extrapolation (Vermeire et al, 1998 andKalberlah et al, 2003;Groeneveld, 2004), for the use of a LOAEL (Falk-Filipsson A, 2007;Gaylor et al, 2000;Dourson et al, 1996;Hasegawa et al, 2010), and for the combination of the different UFs (Chen, 2007;Vermeire, 2001;Hasegawa, 2010). As lognormal distributions are thought to best describe variability and uncertainty in UFs, these distributions have been derived based on NOAEL-ratios from comprehensive toxicological databases.…”

“…Not defined Subchronic to chronic 10 EU (EC, 1996) Industrial chemicals Case-by-case based on expert judgement of scientific information EMEA/ICH (1997) Residual solvents in pharmaceuticals 6-month rodents to chronic 2 3-month rodents to chronic 5 < 3-month rodents to chronic 10 EC (1967) Classification and labelling of chemicals for health effects Subacute to subchronic 3 ECHA (2010) REACH chemicals Subacute to subchronic 3 Subchronic to chronic 2 Subacute to chronic 6 Subacute: 28-day, subchronic: 90-day, chronic: 1.5 -2 years. Vermeire (1999Vermeire ( , 2001 Used the 70 pairs of NOAELS from Groeneveld (2001) 2 Kalberlah (1998Kalberlah ( , 2003 Unspecified number of pairs of NOAELsrats and mice combined (1998) 35 pairs of NOAELs from NTP studies (2003) 1.7 to 2.9 Groeneveld (1999Groeneveld ( , 2004 56 pairs of NOAELS -rat only from the TNO database 70 pairs of NOAELS -rats and mice from the TNO database 2.3 (2.25 to 2.28) Bitsch (2006) 20 pairs of LOAELs from rats and mice 2 Hasegawa (2010) 33 pairs of NOAELs from rats and mice 68 datasets from public reports or papers 1.7…”

Site‐Specific Applications of Probabilistic Health Risk Assessment: Review of the Literature Since 2000

“…Several attempts have been made to derive chemical-specific uncertainty factors and assess uncertainty using probabilistic techniques. For example, Pelekis et al (2003) conducted a probabilistic assessment of adult and child toxicokinetic uncertainty factors; Groeneveld et al (2004) assessed the uncertainty in exposure durations used in the calculation of no observed adverse effects levels (NOAELs). Stern et al (2002) assessed pharmacokinetic variability for methylmercury.…”

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

“…More recently, the use of chemical-specific adjustment factors has been introduced to provide a method for the incorporation of quantitative data on interspecies differences or human variability into the risk assessment process (Meek et al, 2002;IPCS, 2005). These approaches are generally applied to lifetime exposures and are not focused on exposures during specific life stages (Groeneveld et al, 2004). Modifications that account for less-than-lifetime exposures include developing acute and short-term reference exposure values and acute dietary levels (Solecki et al, 2005).…”