Human relevance framework for rodent liver tumors induced by the insecticide sulfoxaflor

Figures & data

Table 1. Key events of rodent CAR-mediated liver tumor MoA.

Key event*	Biomarkers and associated supportive evidence*
(1) CAR activation	Induction of liver Cyp genes/proteins
	Increased liver weight
	Microscopic hepatocellular hypertrophy/cytoplasmic eosinophilia
	Reversibility after cessation of treatment
(2) Increased hepatocellular proliferation	Reversibility after cessation of treatment
(3) Hepatocellular tumors

*Adapted from (Holsapple et al. 2006, Cohen 2010, Elcombe et al. 2014).

Table 2. Sulfoxaflor: temporality and dose response for MoA key events related to CD-1 male mouse liver tumors.

		Temporal
		Key event #1 CAR activation		Key event #2
	Dose (ppm)	Biomarker Cyp2b10 transcripts and protein 7–90 days	Associated event: increased liver weights/hypertrophy 7–90 days	Hepatocellular proliferation 7 days	Increased hepatocellular tumors 18 months
Dose	25				–
	100		–		–
	300	+	–
	500	+	–	+
	750	+	+	+	+
	≥ 1250*		+
	750 KO	–	–	–
	750 HU	+	+	–

KO – CAR/PXR knock-out C57Bl6 mouse model, HU – CAR/PXR humanized knock-in C57Bl6 mouse model.

+ indicates effect present.

− indicates effect absent at indicated duration of treatment.

Blank cell = no data.

*Includes similar results from 1500 ppm and 3500 ppm.

Table 3. Sulfoxaflor: temporality, dose response, and reversibility for MoA key events related to male F344 rat liver tumors.

		Temporal
		Key event #1 CAR activation		Key event #2
	Dose (ppm)	Biomarker Cyp2b10 transcripts and protein 3–7 days	Associated increased liver weights/hypertrophy 7–90 days	Hepatocellular proliferation 7 days	Associated liver hypertrophy after recovery 90 days Plus 28 days recovery	Increased hepatocellular tumors 2 years
Dose	25					–
	100	–	–	–		–
	500					+
	750	+	+	+
	1000		+
	1500	+	+	+	–
	2000		+

+ indicates effect present.

− indicates effect absent at indicated duration of treatment.

Blank cell = no data.

Table 4. Summary evaluation for alternative rodent liver MoAs.

	DNA reactivity	AhR or PPARα activation	Cytotoxicity (28–90 days)	Increased apoptosis	Estrogens, statins, metals, infectious
Strength of association	− Ames −in vitro mammalian chrom. abs and gene mutation −in vivo micronuclei	− Targeted gene expression	+ Ind. cell necrosis, ↑ AST, ALT in some studies	− No histopath evidence	−
Consistency of association	−	−	−	–	–
Specificity of association	–	–	–	–	–
Dose-response concordance	− No tumors at lower doses in mice or rats	–	+/− Ind. cell necrosis at high doses, but not at tumorigenic levels	–	–
Temporal relationship	− Late onset tumors	–	–	–	–
Coherence and plausibility	Not plausible; − Coherence	Not plausible; − Coherence	Plausible; − Coherence	Not plausible; − Coherence	Not plausible; − Coherence

+ indicates attribute present.

− indicates attribute absent.

+/− indicates equivocal.

MoA adapted from (Holsapple et al. 2006, Cohen 2010, Elcombe et al. 2014).

Table 5. Concordance analysis of sulfoxaflor rodent liver tumor CAR MoA.

Key event #1: CAR receptor activation Cyp2b biomarker induction Associated liver hypertrophy Key event #2: Hepatocellular proliferation Reversible effects (including specific knockout and humanized mouse data) Increased hepatocellular tumors
Strength of association	+
Consistency of association	+
Specificity of association	+
Dose-response concordance	+
Temporal relationship	+
Coherence and plausibility	+ Plausible; + Coherence

MoA reviewed in Holsapple et al. (2006), Cohen (2010), Elcombe et al. (2014) and primary references therein.

Holsapple MP, Pitot HC, Cohen SM, Boobis AR, Klaunig JE, Pastoor T, et al. (2006). Mode of action in relevance of rodent liver tumors to human cancer risk. Toxicol Sci, 89, 51–6.

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Cohen SM. (2010). Evaluation of possible carcinogenic risk to humans based on liver tumors in rodent assays: the two-year bioassay is no longer necessary. Toxicol Pathol, 38, 487–501.

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Elcombe CR, Peffer RC, Wolf DC, Bailey J, Bars R, Bell D, et al. (2014). Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: a case study with phenobarbital as a model constitutive androstane receptor (CAR) activator. Crit Rev Toxicol, 44, 64–82.

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