Hypothesis-based weight-of-evidence evaluation and risk assessment for naphthalene carcinogenesis

Figures & data

Figure 1. The seven key aspects of the Hypothesis-Based Weight-of-Evidence (HBWoE) approach.

Figure 2. Proposed scheme for naphthalene metabolism and reactive metabolites (adapted from ATSDR 2005). CYP450 = Cytochrome P450 Enzyme(s); GSH = Reduced Glutathione; SG = Glutathione.

Figure 3. Amount of naphthalene metabolized in rat and human dorsal olfactory, ventral respiratory, lung, and liver tissue per inhaled dose in accordance with the hybrid CFD–PBPK model for naphthalene (Campbell et al. 2014).

Table 1. Human AKRs and activity toward naphthalene metabolites.

Human AKR	Tissue distribution/expression	Activity toward naphthalene metabolites
		Oxidation of Diol to Quinone (nmol/min/mg)	Reduction of Quinone to Diol (nmol/min/mg)	Reference
AKR1A1	Kidney > liver > salivary gland > trachea > stomach > duodenum > fetal lung > prostate > placenta > mammary gland > lung > A549 cells	No study identified	6,300	O’Connor et al. 1999
			ND	Shultz et al. 2011
AKR1C1	Liver, small intestine, lung, mammary gland, and prostate	203		Palackal et al. 2002
			< 5	O’Connor et al. 1999
			ND	Shultz et al. 2011
AKR1C2	Liver, small intestine, lung, mammary gland, and prostate	15		Palackal et al. 2002
			80	Shultz et al. 2011
AKR1C3	Liver, small intestine, lung, mammary gland, and prostate	8.5		Palackal et al. 2002
			400	Shultz et al. 2011
AKR1C4	Liver, lung	40		Palackal et al. 2002
			< 5	O’Connor et al. 1999
			ND	Shultz et al. 2011

ND = evaluated but not detected.

Table 2. Key Events in the proposed modes of action for naphthalene-induced carcinogenesis.

Table 3. Comparative Reasoning for Accounts of Naphthalene Carcinogenesis in Rodents and Human Relevance.

Table 4. Points of departure for lesions in naphthalene-exposed rats from NTP (NTP 2000) and Dodd et al. (2012)*.

Nasal tissue	Sex	Lesion	Point of departure (POD) based on Best-fit model estimate			Point of departure (POD) based on average model (AM) estimate				Data Source
			Best-Fit dose–response model	BMD (BMD10)	POD (BMDL10)	Number of Models	AM_BMD	AM_POD	BMDL Range
Ventral respiratory epithelium	Male	Hyperplasia	Weibull	3.252	0.827	6	2.00	0.781	0.261	Dodd et al. 2012
			Logistic	2.760	2.190	6	3.55	1.412	1.550	NTP 2000
		Squamous metaplasia	Gamma	4.529	3.737	7	5.12	3.819	1.515	Dodd et al. 2012
			LogLogistic	1.360	1.030	4	1.89	1.529	1.371	NTP 2000
	Female	Hyperplasia	LogProbit	5.327	4.253	7	4.99	3.843	1.685	Dodd et al. 2012
			LogProbit	3.361	2.162	6	3.51	2.002	2.529	NTP 2000
		Squamous metaplasia	LogProbit	5.253	4.152	7	4.95	3.742	1.541	Dodd et al. 2012
			LogLogistic	1.519	1.148	4	2.06	1.661	1.420	NTP 2000
Olfactory epithelium	Male	Degeneration	LogLogistic	3.364	1.298	7	4.41	1.245	0.207	Dodd et al. 2012
		Hyperplasia	LogLogistic	8.005	1.341	7	6.83	1.601	1.430	Dodd et al. 2012
			LogLogistic	0.077	0.036	1	NA	NA	NA	NTP 2000
	Female	Degeneration	LogLogistic	3.364	1.298	7	4.41	1.245	0.207	Dodd et al. 2012
		Hyperplasia	LogLogistic	3.364	1.298	7	4.41	1.245	0.207	Dodd et al. 2012

BMD = benchmark dose, BMDL₁₀ = 95% lower confidence limit on the benchmark dose (10% response), POD = point of departure, NA = not applicable.

Average Model (AM): The average model estimates are the arithmetic average BMD or BMDL from all models that adequately fit the data.

BMDL Range = Max BMDL – Min BMDL.

*Data are in units of the amount of naphthalene metabolized in the rat (nmol/min-g tissue) (Using md_v.4 estimates).

Figure 4. Two-year (NTP 2000) vs 90-day (Dodd et al. 2012) metabolized dose–response in male and female rats following naphthalene exposure via inhalation (BMR of 10% extra risk for the 0.95 lower confidence limit on the BMD). Figures show the best-fit curve. See supplemental material for all modeling results. (A) Male rat respiratory epithelial hyperplasia dose–response from 2-year study (Logistic); (B) male rat respiratory epithelial hyperplasia dose–response from 90-day study (Weibull); (C) female rat olfactory epithelial hyperplasia dose–response from 2-year study (Log-Logistic with NO FIT); (D) female olfactory epithelial hyperplasia dose–response from 90-day study (Log-Logistic).

Table 5. Summary of BMDs (AM_BMDs), BMDLs (AM_PODs), HECs, and MOEs.

Nasal tissue	Sex	Lesion	BMD	BMDL [PODRat (nmol/min-g tissue)]	HEC (ppm)	HEC (mg/m^3)	MOE
Ventral respiratory epithelium	Male	Hyperplasia	2.00	0.78	0.63	3.30	3706
		Squamous metaplasia	5.12	3.82*	–*	–*	> 63,000^† or not applicable
	Female	Hyperplasia	4.99	3.84*	–*	–*	> 63,000^† or not applicable
		Squamous metaplasia	4.95	3.74*	–*	–*	> 63,000^† or not applicable
Dorsal olfactory epithelium	Male	Degeneration	4.41	1.25	0.99	5.19	5824
		Hyperplasia	6.83	1.60	1.43	7.49	8412
	Female	Degeneration	4.41	1.25	0.99	5.19	5824
		Hyperplasia	4.41	1.25	0.99	5.19	5824

BMD = Benchmark Dose. As shown here, the BMD is equal to the average of the BMDs from all adequately fitting models (AM_BMD from Table 4), BMDL = 95% Lower Confidence Limit on the Benchmark Dose (10% response). As shown here, the BMDL is equal to the average of the BMDLs from all adequately fitting models (AM_POD from Table 4), POD = Point of Departure, HEC = Human Equivalent Concentration, Margin of Exposure (MoE) is the HEC divided by the typical residential exposure level of 0.00017 ppm (0.95 μg/m³).

*Rate of metabolism in the rat precludes calculation of an HEC due to the saturation of metabolism in humans (i.e., > 4.5 nmol/min-g tissue in the dorsal olfactory; > 1.5 nmol/min-g tissue in the ventral respiratory; at > 10.7 ppm continuous exposure) (Campbell et al. 2014).

^†MOE is HEC divided by 10.7 ppm (highest continuous exposure concentration evaluated in the model).

1 ppm = 5.24 mg/m³.

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