Journal of Applied Toxicology

As one of the main extra‐hepatic cytochrome P450 (CYP) enzymes, CYP1A1 has been comprehensively investigated for its ability to metabolize both exogenous and endogenous compounds into their carcinogenic derivatives. These derivatives are linked to cancer initiation and progression. The compound benzo‐a‐pyrene (BaP), a copious and noxious compound present in coal tar, automobile exhaust fumes, cigarette smoke and charbroiled food, is metabolised by CYP1A1 and has been studied in great detail. Other compounds reliant on the same enzyme for their activation include 7,12 dimethylbenz(a)anthracene (DMBA) and heterocyclic amine, 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP). This review takes an in‐depth look at a number of phytochemicals, plant extracts and a few synthetic compounds that have been researched and deemed potential chemopreventives via their interaction with the activity and expression of CYP1A1. It will also review a useful active site model of CYP1A1. Based on inhibitors of CYP1A1 that have demonstrated in vivo use as chemopreventors, CYP1A1 is a useful initial target for screening compounds with such potential, with the use of rapid in vitro and/or in silico assessments. Chemoprevention is a means by which healthy tissues are protected via the prevention, inhibition or reversal of carcinogenesis. This review focuses on one important pathway of carcinogenesis and identifies the important role that CYP1A1 plays in that pathway. It is hoped that highlighting the importance of such a key target, will help revive further research into and application of inhibitors of CYP1A1 towards generating improved chemopreventors. Copyright © 2014 John Wiley & Sons, Ltd.

Half of the world's population still relies on solid fuels to fulfill its energy needs for cooking and space heating, leading to high levels of household air pollution (HAP), adversely affecting human health and the environment. A cross‐sectional cohort study was conducted to investigate any associations between: (1) HAP metrics (mass concentration of particulate matter of aerodynamic size less than 2.5 μm (PM_2.5), lung‐deposited surface area (LDSA) and carbon monoxide (CO)); (2) a range of household and socio‐demographic characteristics; and (3) lung function for women and children exposed daily to biomass cookstove emissions, in rural southern India. HAP measurements were collected inside the kitchen of 96 households, and pulmonary function tests were performed for the women and child in each enrolled household. Detailed questionnaires captured household characteristics, health histories and various socio‐demographic parameters. Simple linear and logistic regression analysis was performed to examine possible associations between the HAP metrics, lung function and all household/socio‐demographic variables. Obstructive lung defects (forced vital capacity (FVC) ≥ lower limit of normal (LLN) and forced expiratory volume in 1 second (FEV₁)/FVC < LLN) were found in 8% of mothers and 9% of children, and restrictive defects (FVC < LLN and FEV₁/FVC ≥ LLN) were found in 17% of mothers and 15% of children. A positive association between LDSA, included for the first time in this type of epidemiological study, and lung function was observed, indicating LDSA is a superior metric compared to PM_2.5 to assess effects of PM on lung function. HAP demonstrated a moderate association with subnormal lung function in children. The results emphasize the need to look beyond mass‐based PM metrics to assess fully the association between HAP and lung function.

T‐2 toxin is now considered to be related to bone malformation such as incomplete ossification, absence of bones and fused bones. In this study, primary cultures of chicken tibial growth plate chondrocytes (GPCs) were treated with various concentrations of T‐2 toxin (5, 50, and 500 n m) in the absence and presence of N‐acetyl‐cysteine (NAC) to investigate the effects of the antioxidant NAC on T‐2 toxin‐induced toxicity. Our results showed that T‐2 toxin markedly decreased cell viability, alkaline phosphatase activity and glutathione content (P < 0.05). In addition, T‐2 toxin significantly increased reactive oxygen species levels and malondialdehyde in a dose‐dependent manner. However, the T‐2 toxin‐induced cytotoxicity was reversed, in part, by the antioxidant NAC (P < 0.05). These results suggest that T‐2 toxin inhibits the proliferation and differentiation of GPCs in vitro by altering cellular homeostasis and NAC can protect GPCs against T‐2 toxin cytotoxicity by reducing the T‐2 toxin‐induced oxidative stress. Copyright © 2011 John Wiley & Sons, Ltd.

The properties of trivalent and hexavalent chromium are reviewed with respect to acute and chronic oral toxicity, dermal toxicity, systemic toxicity, toxicokinetics, cytotoxicity, genotoxicity and carcinogenicity. The hexavalent chromium compounds appear to be 10–100 times more toxic than the trivalent chromium compounds when both are administered by the oral route. Dermal irritancy and allergy are more frequently caused by contact with soluble hexavalent chromium compounds. The cytotoxicity of soluble and insoluble hexavalent chromium compounds to fibroblasts is 100‐1000 times greater than that demonstrated by trivalent chromium compounds. In short‐term tests, the hexavalent chromium compounds demonstrated genotoxic effects four times more frequently than did the trivalent chromium compounds. Carcinogenicity appears to be associated with the inhalation of the less soluble/insoluble hexavalent chromium compounds. The toxicology of chromium does not reside with the elemental form. It varies greatly among a wide variety of very different chromium compounds. Oxidation state and solubility are particularly important factors in considering the toxicity of chromium with respect to its chemical speciation.

Several types and modifications of nose‐only inhalation chambers for exposing rodents are described. The improvement of this ‘flow‐past’ ‐like nose‐only exposure system is that it is modular, i.e. it can be used for acute studies with a maximum of 20 rodents (one segment) or for chronic inhalation studies with 100 (or more) rodents per chamber with five (or more) segments. Another goal was to design a nose‐only exposure system that provides maximal computer support and automatization, as well as robust aerosol collection conditions. The evaluation of the five‐segment chamber, charged with 98 rats, revealed that a flow rate of 0.75 I air min⁻¹ or approximately 2.5 times the rat minute ventilation volume per exposure port is sufficient to provide homogeneous temporal and spatial exposure conditions. Also, the aerosol size distribution was constant throughout the chamber. Experimental data suggest that computer‐controlled sampling of the test atmosphere up to ca. 6 I air min⁻¹ did not alter the flow dynamics of the exposure system. The nose‐only inhalation chamber developed is suitable for short‐term and long‐term inhalation toxicity studies using small laboratory rodents with minimal consumption of test compound.

The respiration of naive F344 rats confined in nose‐only inhalation exposure tubes was measured to obtain data for normal adult rats of different ages and to evaluate the tubes for exposures lasting several hours. Exposure tubes were modified for use as volume‐displacement plethysmographs. Respiration of 10 male and 10 female rats at 3, 6, 12 and 24 months of age was measured in the tubes during simulated exposures of up to 6 h duration. Measurements included respiratory frequency, tidal volume, minute volume and body surface temperature. The mean respiratory frequencies of 3, 6, 12 and 24 month old rats during the first hour of exposure were 172, 152, 123 and 136 breaths min⁻¹, respectively. Minute volumes were 1.40, 089, 0.67 and 0.82 ml g⁻¹ body weight, respectively. Both frequency and minute volume g⁻¹ body weight were significantly greater for the youngest group, declined with age to 12 months and then increased at 24 months. Minute volumes g⁻¹ body weight were similar for males and females. Minute volume and respiratory frequency of 3 and 12 month old rats declined progressively between 1 and 6 h of confinement in the tubes. Surface temperature did not increase after the first hour. The age and sex‐specific data provide a basis for predicting respiration of naive tube‐confined rats during inhalation exposures to non‐irritating materials.

Directed‐flow nose‐only exposure systems are designed and operated so that the genuine test atmosphere is dynamically delivered to each exposure port and exhaled air from exposed animals is immediately exhausted without the possibility of other animals rebreathing this atmosphere. This technique is particularly useful for preventing uncontrolled changes of exposure atmospheres, stimulating breathing activity due to the rebreathing of exhaled carbon dioxide, and the conserving a test material that is available only in limited quantities. The intricate relationship of the delivered flow of air at each exposure port relative to the respiratory minute volume of the exposed animal appears to be critical for the state‐of‐the‐art performance of directed‐flow nose‐only exposure systems. This analysis revealed that the determination of carbon dioxide concentrations at different inhalation chamber locations, including exposure ports, is a simple and cost‐effective procedure to evaluate whether the rebreathing of atmospheres can be excluded. It has been shown that directed‐flow systems need to be operated at an exposure air flow rate greater than 2.5 times the respiratory minute volume of the exposed animal or optimally ∼0.75 l min⁻¹ per rat exposure port (∼3.75 times the minute volume of young adult rats) to prevent higher CO₂‐concentrations occurring. Copyright © 2007 John Wiley & Sons, Ltd.

Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits potential anti‐tumor activity against many tumor cell lines. This study aims to examine the anti‐tumor activity of OA on pancreatic cancer cells and its potential molecular mechanism. The results showed that the proliferation of Panc‐28 cells was inhibited by OA in a concentration‐dependent manner, with an IC₅₀ (The half maximal inhibitory concentration) value of 46.35 µg ml⁻¹, as determined by MTT (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay. The cell cycle was arrested in S phase and G2/M phase by OA. The study also showed that OA could induce remarkable apoptosis, evidenced by an increased percentage of early/late apoptotic cells, DNA ladder and nuclear morphology change. Further study revealed that OA could induce Reactive Oxygen Species (ROS) generation, mitochondrial depolarization, release of cytochrome C, lysosomal membrane permeabilization and leakage of cathepin B. The expression of apoptosis‐correlated proteins was also affected in cells treated with OA, including activation of caspases‐3/9 and cleavage of PARP. Further study confirmed that ROS scavenger vitamin C could reverse the apoptosis induced by OA in Panc‐28 cells. Our results provide evidence that OA arrests the cell cycle and induces apoptosis, possibly via ROS‐mediated mitochondrial and a lysosomal pathway in Panc‐28 cells. Copyright © 2012 John Wiley & Sons, Ltd.