Health Effects of Chemical Mixtures: Benzo[a]pyrene and Arsenic Hasmik Hakobyan, Elizabeth Vaccaro and Hollie Migdol Department of Environmental & Occupational Health, California State University, Northridge Abstract Routes of Exposure Metabolism of Benzo[a]pyrene and Arsenic Arsenic and benzo[a]pyrene (BaP) are ubiquitous compounds commonly found throughout the environment. This poster is a review of the current literature examining the combined effects of arsenic and BaP to determine the mechanism of their synergistic qualities. Being exposed to both arsenic and BaP simultaneously in the environment is very likely. Vehicle exhaust, volcanoes, cigarette smoke, air pollution, industrial processes contaminated water and charred meats can contribute to the co-exposure to arsenic and BaP. The carcinogenicity of BaP occurs subsequent to the metabolic activation of the compound resulting in DNA damage via DNA-adduct formation. The literature indicates that the co-exposure to arsenic and BaP causes a synergistic reaction between to the two compounds, as arsenic potentiates BaP-DNA adducts. BaP DNA adduct formation. [18] Introduction Arsenic occurs in the environment naturally and it is Arsenic manmade. Arsenic sources are algaecides, mechanical cotton harvesting, glass manufacturing, herbicides, and nonferrous Dermal: Dermal exposure may lead to illness, but to a lesser extent alloys [2]. Arsenic trioxide may be found in pesticides and than ingestion or inhalation. [4] [9] defoliants and as a contaminant of moonshine whiskey [2]. Presently, arsenic is widely used in the electronics industry in Ingestion: Main intake of arsenic is through ingestion of food the form of gallium arsenide and arsine gas as components in containing arsenic. Average daily intake of arsenic by adults in US is semiconductor devices. Arsenic production no longer occurs 40mg per day. [2]. Meat/fish/poultry accounts for 80% of arsenic in the US. Arsenic has been phased out of domestic intake. Areas near geothermal activity have highest levels of pesticides, but commercial use of imported arsenic is still groundwater arsenic concentrations [2]. Toxicological Endpoints high [2]. Arsine gas, the most toxic arsenical (acute exposures), is used commercially in the microelectronics Inhalation: Inhalation of arsenic is due to burning of fossil fuel industry, and in metallurgical and mining processes. Arsenic containing arsenic, cotton gins, glass manufacturing operations, is classified by the International Agency for Research on pesticide manufacturing facilities, smelters, and tobacco smoke[2]. Cancer (IARC) as a Group 1, carcinogenic to humans, compound [7]. Benzo[a]pyrene Benzo[a]pyrene (BaP) is a five-ring polycyclic aromatic Dermal: BaP enters the body when skin comes in contact with soil hydrocarbon (PAH). PAHs are a by-product of the incomplete that contains high levels of BAP (hazardous waste site) or with used combustion of organic material and are likely to be found in crankcase oil or creosote that contain BAP. various concentrations in the environment. There are over [13] 100 PAHs that are naturally occurring and found at Ingestion: BaP has been found in some drinking water supplies in background levels in uncontaminated regions. The chemical the US. Food grown in contaminated soil or air may also contain BaP. structures of PAHs are closely related and they are likely to Cancer is the toxicological endpoint of concern when discussing the co-exposure to arsenic and BaP. Co- Cooking meat or other food at high temperatures, which happens have similar reactions inside the body following exposure. exposure to Arsenic and BaP can lead to the development of cancer during the initiation phase of during grilling or charring, increases the amount of BAP in the food. There are 17 PAHs that are studied more than others due to carcinogenesis. Arsenic increases the ability of BaP to form DNA-adducts (maier). The formation of DNA- the probability of being exposed to these and the level of Inhalation: Most common route of exposure to BaP. Inhalation adducts can lead to genetic mutations during DNA transcription which can lead to the development of harm they may induce on exposed humans [1]. One of these exposure to BAP can occur when molecules attach to dust and other cancer cells. 17 PAHs is BaP, which is classified by the International particles in the air. Sources include cigarette smoke, vehicle Agency for Research on Cancer (IARC) as a Group 1, exhausts, asphalt roads, coal, coal tar, wildfires, agricultural burning, carcinogenic to humans, compound [8]. The link between residential wood burning, municipal and industrial waste BaP exposure and cancer development was first discovered incineration, and hazardous waste sites [1]. in 1775 due to incidence of scrotum cancer in chimney sweepers [1]. Chemical Structures Benzo[a]pyrene Arsenate Arsenite 3- 3- C20H12 AsO 4 AsO 3 [14] Environmental Fate & Transport Mechanisms of Toxicity Arsenic Soil: Low levels of naturally occurring mineral arsenic are present in Arsenic soil. Mineral ore and erosion of natural land sources, discarded mine Possible mechanisms of arsenic toxicity include oxidative stress, DNA fragmentation, apoptosis and functional changes and mill tailings, arsenic- containing materials transported via rain of ion channels. Mitochondrial disruption, caspase activation, MAPK signaling and p53 may be the pathways for arsenic induced apoptosis. During arsenic metabolism the generation of various types of reactive oxygen species (ROS) result in drinking water and soil contaminations. such as superoxide anion radical (O2 − • ), singlet oxygen (O2 ), peroxyl radical (ROO• ) and hydrogen peroxide (H2O2 ) Air: Arsenic is released in the air by volcanoes and dispersion in the occurs. It also initiates the formation of dimethylarsinic radicals [(CH3 )2 As• ], dimethylarsinic peroxyl radicals [(CH3 )2 environment from mining and commercial use. In industry arsenic is AsOO• ] and nitric oxide (NO• ) [3]. Arsenic is not a known potent mutagen [11]. Multiple studies have reported that a byproduct of the smelting process for metal ores such as cobalt, arsenic exposure decreases GSH level especially the cardiac glutathione [3]. gold, lead, nickel, and zinc. Water: It enters the environment via ground water, mineral ore, Benzo[a]pyrene geothermal processes. Artesian and tube wells supplied by BaP requires bioactivation in order to demonstrate its genotoxic effects. This bioactivation is catalyzed by the geologically contaminated aquifers result in drinking water cytochrome P450 enzymes creating highly reactive diol-epoxides that form DNA adducts which can lead to mutations contamination. through errors in DNA replication. The genotoxic effects of BaP occur in genes linked to pathways of p53 function. The Food: Arsenic may be found in foods such as seafood, crustaceans, normal function of p53 control includes the regulation of apoptosis, cell cycle regulation, senescence, energy etc. Organic forms of arsenic are considered nontoxic arsenic which metabolism, angiogenesis, cell differentiation and immune response [17]. BAP is a well known mutagen which can induce a variety of DNA changes including deletions, transversions and transitions [6]. BaP adduct formation is are found in seafood [2]. dependent on the presence of the cytochrome p450 enzyme CYP1A1 [11]. BaP is known to produce ROS that can induce DNA adduct formation and subsequent genetic mutation. This DNA-adduct formation is considered a pivotal Benzo[a]pyrene genetic risk factor for BaP initiated carcinogenesis [10]. Soil: BaP can attach tightly to particles. BaP can evaporate from surface soils to air. In soil it can contaminate underground water. BAP [12] content on plants and animals living on the land or in water can be Arsenic + BaP many times higher than the content of BAP in soil or water. Suggested mechanisms of toxicity following co-exposure to arsenic and BaP include: Air: BAP enters the environment via volcanoes, forest fires, • DNA Methylation- Arsenic increases DNA methylation which can have an effect on gene transcription by producing residential wood burning, and exhaust from vehicles. In the air, BAP is a negative control of gene regulation. In the presence of BaP, it is possible that DNA methylation occurs more either attached to dust particles or as solids in soil or sediment. They frequently than with arsenic exposure alone. can travel long distances before they return to earth in rainfall or • Cytochrome p450 enzymes- BaP is metabolized by the cytochrome p450 enzyme,CYP1A1 and CYP1B1. Another particle settling. possible mechanism of co-toxicity includes increasing the enzymatic activity of CYP1A1/1B1 resulting in an Water: BAP can enter surface water through discharges from increase in the number of BaP metabolites available to form DNA-adducts. Although it was shown that arsenic did industrial plants and waste water treatment plants, and they can be not enhance the metabolic activity of the CYP1A1 enzyme on BaP [11]. It is clear that co-toxicity does not occur released to soils at hazardous waste sites if they escape from storage during the phase I metabolism of B a P. • Glutathione- Glutathione has been demonstrated to protect against arsenic toxicity [11]. Arsenic could potentially containers. The movement of PAHs in the environment depends on deplete cellular glutathione which plays a significant role in the conjugation reactions of BaP metabolites which properties such as how easily they dissolve in water, and how easily could potentiate