Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance

Figures & data

Figure 1. Conceptual representation of WHO/IPCS’ problem formulation and its relationship with various tiers of increasing complexity of hazard characterization.

Figure 2. Relationship of the consideration of uncertainty relevant to problem formulation and tiered assessment (amended from WHO/IPCS 2014).

Figure 3. Subdivision of default uncertainty factors into toxicokinetic and toxicodynamic subfactors for the derivation of CSAF.

Figure 4. Evolutionary timeline of the major developments surrounding the WHO/IPCS (2005) CSAF Guidance.

Figure 5. Continuum between default uncertainty factors and CSAF and relationship with fully biological-based adjustment factors, as a function of the available data. The directional arrow and intensity of the gray shade corresponds to increased robustness and decreased uncertainty.

Table

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Table 1. Some CSAF examples not retrieved by the original literature search terms.

Chemical (reference)	Factor(s) evaluated	Methodology	Term(s) used in publication	Original literature search term(s) not cited
Acrylamide (Sweeney et al. 2010)	Interspecies TK	PBPK model	“PBPK” “risk assessment” “uncertainty”	”Uncertainty factor”
Boron (Hasegawa et al. 2013)	Interspecies TK and TD Human Variability TK and TD	Dose metric ratios	“chemical specific UF” “human variability UF”	”Chemical-specific adjustment factor“, “CSAF”, “human toxicokinetic(s) adjustment factor”
Chloroform (Liao et al. 2007)	Interspecies TK and TD	PBPK/PD model	“pharmacokinetics” “pharmacodynamics” “cross-species”	”Toxicokinetic(s)" ”Toxicodynamic(s)” “Interspecies”
Chromium (Thompson et al. 2014)	Interspecies TK	PBPK model	“interspecies variation” “PBPK” “risk assessment” “uncertainty”	”Uncertainty factor”
Isopropanol and major metabolite, acetone (Gentry et al. 2003, 2002)	Interspecies TK	PBPK model	“PBPK” “risk assessment” “pharmacokinetics” “pharmacodynamics”	”Toxicokinetic(s)" ”Toxicodynamic(s)”

Table

Supplemental Table ID	Title
Table A1	Regulatory Agency-derived Interspecies and/or Human Variability CSAF based on TK or TD Ratios (n = 18)
Table A2	Regulatory Agency-derived Interspecies and/or Human Variability CSAF based on PBPK Models (n = 16)
Table B	Non-regulatory Assessments with CSAF or Departure from Default Interspecies and/or Human Variability Uncertainty Factor (n = 30)
Table C	CSAF Investigating the Human Variability TK Subfactor (n = 47)
Table D	Considered but not Adopted Regulatory Agency-derived CSAF (or Departure from Default) (n = 11)
Table E	Some Categorical Adjustment Factor Examples (n = 7)
Table F	Joint FAO/WHO Expert Committees (JECFA or JMPR) Categorical CSAF Examples (n = 6)

Table 2. Geographic distribution of CSAF used in regulatory decision-making compared with non-regulatory or investigative CSAF^a.

Region	USA	Canada	Europe	Asia
Used in regulatory decision-making (Supplemental Tables A1/A2)^b	8 (TK)^c 5 (TD)^d 9 (PBPK)	1 (TK) 1 (TD) 7 (PBPK)^e	3 (TK) – –	– – –
Non-regulatory-derived risk assessments (Supplemental Table B)^b	5 (TK) 1 (TD) 22 (PBPK)	– – –	– – –	1 (TK) 1 (TD) –
Human variability TK subfactor (Supplemental Table C)^b^,^f	4 (PBPK-Pr) 19 (PBPK-D) – –	9 (PBPK-Pr) 1 (PBPK-D) 5 (SS-Pr) –	6 (PBPK-Pr) 2(PBPK-D) – 1 (SS-D)	– – – –
CSAF considered by regulatory entity but not adopted (Supplemental Table D)	1 (TK) – 2 (PBPK)	– – 1 (PBPK)	4 (TK) – –	1 (TK) 1 (TD) –

TK or TD : ratio-based CSAF (either interspecies or human variability); excludes semi-quantitative factors and factors not subdivided; PBPK: physiologically-based pharmacokinetic model.

^a Only regions with identified CSAF are represented (all entries in Asia column are for boron).

^b Includes same chemicals assessed by different groups.

^c Four are perfluorinated chemicals and duplicates (US EPA or US state authority).

^d Three are N-methylcarbamates (EPA).

^e Excludes four draft Health Canada assessments for perfluorinated chemicals since documents or details were not available.

^f All are PBPK or steady-state (SS) models: Pr: probabilistic; D: deterministic; risk assessment context (e.g. key study, critical effect) not always provided.

^h Some overlap with Tables A and B, such as NMP (USA) and boron (Asia), respectively.

WHO/IPCS (World Health Organization/International Programme on Chemical Safety). 2014. Guidance document on evaluating and expressing uncertainty in hazard characterization. (IPCS harmonization project document no. 11). Geneva, Switzerland. Available from: http://www.who.int/ipcs/methods/harmonization/uncertainty_in_hazard_characterization.pdf

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Sweeney LM, Kirman CR, Gargas ML, Carson ML, Tardiff RG. 2010. Development of a physiologically-based toxicokinetic model of acrylamide and glycidamide in rats and humans. Food Chem Toxicol. 48:668–685.

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Hasegawa R, Hirata-Koizumi M, Dourson ML, Parker A, Ono A, Hirose A. 2013. Safety assessment of boron by application of new uncertainty factors and their subdivision. Regul Toxicol Pharmacol. 65:108–114.

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Liao KH, Tan YM, Conolly RB, Borghoff SJ, Gargas ML, Andersen ME, Clewell HJ. 2007. Bayesian estimation of pharmacokinetic and pharmacodynamic parameters in a mode‐of‐action‐based cancer risk assessment for chloroform. Risk Anal. 27:1535–1551.

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Thompson CM, Kirman CR, Proctor DM, Haws LC, Suh M, Hays SM, Hixon JG, Harris MA. 2014. A chronic oral reference dose for hexavalent chromium‐induced intestinal cancer. J Appl Toxicol. 34:525–536.

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Gentry PR, Covington T, Clewell H, Anderson M. 2003. Application of a physiologically based pharmacokinetic model for reference dose and reference concentration estimation for acetone. J Toxicol Environ Health Part A. 66:2209–2225.

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Gentry PR, Covington TR, Andersen ME, Clewell HJ. 2002. Application of a physiologically based pharmacokinetic model for isopropanol in the derivation of a reference dose and reference concentration. Regul Toxicol Pharmacol. 36:51–68.

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