The limitations of using the NTP chronic bioassay on vanadium pentoxide in risk assessments.

Regulatory interest in assessing the health effects of vanadium compounds is hindered by the limited chronic toxicity data available. The National Toxicology Program (NTP) conducted a robust chronic inhalation bioassay of crystalline vanadium pentoxide (VO), but this study has noteworthy limitations. Multiple dose range-finding studies were conducted at two separate laboratories that showed cross-laboratory differences in lung pathology (inflammation) in both species and likely complicated dose-selection.

Quantification of Kras mutant fraction in the lung DNA of mice exposed to aerosolized particulate vanadium pentoxide by inhalation.

This study investigated whether Kras mutation is an early event in the development of lung tumors induced by inhalation of particulate vanadium pentoxide (VP) aerosols. A National Toxicology Program tumor bioassay of inhaled particulate VP aerosols established that VP-induced alveolar/bronchiolar carcinomas of the B6C3F1 mouse lung carried Kras mutations at a higher frequency than observed in spontaneous mouse lung tumors. Therefore, this study sought to: (1) characterize any Kras mutational response with respect to VP exposure concentration, and (2) investigate the possibility that amplification of preexisting Kras mutation is an early event in VP-induced mouse lung tumorigenesis.

Evaluation of cII mutations in lung of male Big Blue mice exposed by inhalation to vanadium pentoxide for up to 8 weeks.

Chronic inhalation of vanadium pentoxide (V2O5) increases the incidence of alveolar/bronchiolar tumors in male and female B6C3F1 mice at 1, 2, or 4 mg/m(3). The genotoxicity of V2O5 has been extensively investigated in the literature with mixed results. In general, tests for gene mutations have been negative.

Using gene expression profiling to evaluate cellular responses in mouse lungs exposed to V2O5 and a group of other mouse lung tumorigens and non-tumorigens.

Many compounds test positive for lung tumors in two-year NTP carcinogenicity bioassays in B6C3F1 mice. V2O5 was identified as a lung carcinogen in this assay, leading to its IARC (International Agency for Research on Cancer) classification as group 2b or a "possible" human carcinogen. To assess potential tumorigenic mode of action of V2O5, we compared gene expression and gene ontology enrichment in lung tissue of female B6C3F1 mice exposed for 13 weeks to a V2O5 particulate aerosol at a tumorigenic level (2.

Vanadium pentoxide: risk assessment implications of a treatment- but not dose-related tumorigenic response in B6C3F1 mice.

The US Environmental Protection Agency (USEPA) is currently conducting a toxicological review of vanadium pentoxide (V2O5). As part of that effort, the Agency will need to address the fact that while a National Toxicology Program (NTP) chronic inhalation bioassay of V2O5 produced clear evidence of treatment-related lung tumors in both male and female B6C3F1 mice, neither of these responses were dose-related across the groups exposed to 1, 2, and 4mg/m(3). While lung tumor incidence was significantly elevated in all three exposed groups relative to that in the control groups, it was essentially flat across them.

Vanadium pentoxide: use of relevant historical control data shows no evidence for a carcinogenic response in F344/N rats.

The National Toxicology Program (NTP) chronic inhalation bioassay of vanadium pentoxide (V(2)O(5)) produced "clear" evidence of lung tumors in B6C3F1 mice, but only "some" and "equivocal" evidence in male and female F344/N rats, respectively. No significant pairwise differences or trends with V(2)O(5) concentration in male or female rat poly-3-adjusted tumor incidence were reported. The "some" and "equivocal" evidence descriptors arose from comparisons of V(2)O(5)-exposed group incidence rates with NTP-2000- and NIH-07-fed historical control (HC) group incidence ranges.

Dichlorvos--a comprehensive review of 11 rodent carcinogenicity studies.

Dichlorvos (DDVP) has been studied in 11 cancer bioassays. Only two studies, the National Toxicology Program (NTP) rat and mouse studies, show any indication of carcinogenic effects and these results, an increase in mononuclear cell leukemia in the rat and an increase in forestomach tumors in the mouse, appear to be related to the corn oil vehicle. The increase in mononuclear cell leukemia was confined to the male rat, was not dose-related, did not show an earlier onset than the controls, had no effect on survival, was within the range seen in historical controls, and was not confirmed in five other rat studies, four of which used higher doses.

Humans appear no more sensitive than laboratory animals to the inhibition of red blood cell cholinesterase by dichlorvos.

Inhibition of red blood cell (RBC) cholinesterase is a consistent and sensitive indicator of exposure to dichlorvos (DDVP). Absent human data, default 10-fold adjustment factors for potential interspecies and intraspecies sensitivity differences would be used in developing a reference dose from the no observed effect levels for this endpoint obtained in toxicological assessments of laboratory animals. However, many studies of the cholinesterase-inhibiting effects associated with DDVP exposure have been conducted in humans, including healthy male volunteers, other healthy subpopulations, and diverse clinical subpopulations.