Physiologically Based Biokinetic (PBBK) Model for Safrole Bioactivation and Detoxification in Rats

Abstract

A physiologically based biokinetic (PBBK) model for alkenylbenzene safrole in rats was developed using in vitro metabolic parameters determined using relevant tissue fractions. The performance of the model was evaluated by comparison of the predicted levels of 1,2-dihydroxy-4-allylbenzene and 1'-hydroxysafrole glucuronide to levels of these metabolites reported in the literature to be excreted in the urine of rats exposed to safrole and by comparison of the predicted amount of total urinary safrole metabolites to the reported levels of safrole metabolites in the urine of safrole exposed rats. These comparisons revealed that the predictions adequately match observed experimental values. Next, the model was used to predict the relative extent of bioactivation and detoxification of safrole at different oral doses. At low as well as high doses, P450 mediated oxidation of safrole mainly occurs in the liver in which 1,2-dihydroxy-4-allylbenzene was predicted to be the major P450 metabolite of safrole. A dose dependent shift in P450 mediated oxidation leading to a relative increase in bioactivation at high doses was not observed. Comparison of the results obtained for safrole with the results previously obtained with PBBK models for the related alkenylbenzenes estragole and methyleugenol revealed that the overall differences in bioactivation of the three alkenylbenzenes to their ultimate carcinogenic 1'-sulfooxy metabolites are limited. This is in line with the generally less than 4-fold difference in their level of DNA binding in in vitro and in vivo studies and their almost similar BMDL(10) values (lower confidence limit of the benchmark dose that gives 10% increase in tumor incidence over background level) obtained in in vivo carcinogenicity studies. It is concluded that in spite of differences in the rates of specific metabolic conversions, overall the levels of bioactivation of the three alkenylbenzenes are comparable which is in line with their comparable carcinogenic potential.

Carcinogenic compounds in alcoholic beverages: an update

“…BMDL for oral exposure was derived by route-to-route extrapolation (US EPA 2003) d No usable BMD modelling for oral exposure was identified in the literature. The no effect level (NOEL), no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL) are used in these cases instead e A range of "approximately 3-29 mg/kg bw/day" was provided as BMDL 10 for safrole (Martati et al 2011). As no further rationale was provided in the study, we chose the minimum of this range to provide a conservative assessment 0.029 Peto et al (1991a, b) Ochratoxin A Kidney adenoma and carcinoma in male rats (oral) Barlow et al (2008) 0.025 NTP (1989) Pulegone Urinary bladder tumours in rats (oral) EMA (2014) LOAEL: 20 d NTP (2011b)…”

“…Hepatic tumours in mice (oral) Martati et al (2011) those with MOE below 10,000 such as lead, ethyl carbamate, cadmium, benzene, arsenic and acetaldehyde. Finally, we also see no scientific basis for advertising claims that certain alcoholic beverages are more or less carcinogenic than others (e.g.…”

Comparative risk assessment of carcinogens in alcoholic beverages using the margin of exposure approach

“…37 7 A range of ''approximately 3-29 mg/kg bw/day'' was provided as BMDL 10 for safrole. 41 As no further rationale was provided in the study, we chose the minimum of this range to provide a conservative assessment. a A standard drink in Canada is considered to have a total of 13.6 g of alcohol.…”

Levels of Genotoxic and Carcinogenic Ingredients in Plant Food Supplements and Associated Risk Assessment

“…For estragole, the formation of the ultimate carcinogenic metabolite was predicted to show a 2-fold relative increase when comparing a low dose (0.05 mg/kg bw) with a high dose (300 mg/kg bw) of estragole [76]. Whereas for safrole, the PBK model predicted that the increase in the relative formation of the ultimate carcinogen with the dose is negligible [77].…”