Organophosphorous pesticides research in Mexico: epidemiological and experimental approaches

Toxicology Mechanisms and Methods, 2011; 21(9): 681–691 © 2011 Informa Healthcare USA, Inc. ISSN 1537-6516 print/ISSN 1537-6524 online DOI: 10.3109/15376516.2011.602130

REVIEW ARTICLE

Organophosphorous pesticides research in Mexico: epidemiological and experimental approaches Toxicology Mechanisms and Methods Downloaded from informahealthcare.com by Cinvestav on 10/20/11 For personal use only.

Sánchez-Guerra M1, Pérez-Herrera N2, and Quintanilla-Vega B1 Departamento de Toxicología, CINVESTAV-IPN, México, and 2Unidad Interinstitucional de Investigación Clínica y Epidemiológica, Facultad de Medicina, Universidad Autónoma de Yucatán, Mérida, Yucatán, México 1

Abstract Non-persistent pesticides, such as organophosphorous (OP) insecticides have been extensively used in Mexico, and becoming a public health problem. This review presents data of OP use and related toxicity from epidemiological and experimental studies conducted in Mexico. Studies in agricultural workers from several regions of the country reported moderate to severe cholinergic symptoms, including decreased acetylcholinesterase (AChE) activity (the main acute OP toxic effect that causes an over accumulation of the neurotransmitter acetylcholine), revealing the potential risk of intoxication of Mexican farmers. OP exposure in occupational settings has been associated with decreased semen quality, sperm DNA damage and as endocrine disrupter, particularly in agricultural workers. Alterations in female reproductive function have also been observed, as well as adverse effects on embryo development by prenatal exposure in agricultural communities. This illustrates that OP exposure represents a risk for reproduction and offspring well-being in Mexico. The genotoxic effects of this group of pesticides in somatic and sperm cells are also documented. Lastly, we present data about gene-environmental interactions regarding OP metabolizing enzymes, such as paraoxonase-1 (PON1) and its role in modulating their toxicity, particularly on semen quality and sperm DNA integrity. In summary, readers will see the important health problems associated with OP exposure in Mexican populations, thereby the need of capacitation programs to communicate farmers the proper handling of agrochemicals to prevent their toxic effects and of more well designed human studies to support data of the current situation of workers and communities dedicated to agriculture activities. Keywords: Organophosphorous pesticides, reproductive toxicity, neurotoxicity, gene-environment interaction

Pesticides use in Mexico The use of pesticides in Mexico began almost 60 years ago, however, the risk to public health associated with pesticide exposure was not recognized until two decades ago, and the efforts to get international guidelines began when Mexico joined the Rotterdam Convention (1998). In Mexico, pesticides regulation is determined by the United Mexican States Constitution, involving several government agencies such as Federal Commission for the Protection against Sanitary Risks (COFEPRIS), the Ministry of Health (SSA), the Ministry of Environment and Natural Resources (SEMARNAT), the Ministry of Agriculture, Livestock, Rural Development, Fisheries and Food (SAGARPA), and the Ministry of Labor and Social Welfare (STPS). Thus, an interagency commission CICOPLAFEST (Commission for

the Control of the Processing and Use of Pesticides, Fertilizers, and Toxic Substances) formed in 1987 by the Mexican government coordinates and administers chemical control legislation, including registry, importation and exportation of pesticides. According to CICOPLAFEST (2004), OP pesticides are used in agriculture, industry, and gardening, and urban pest control and the toxicological classes of different formulations belong to I–IV groups. At the moment, there are 236 certified companies in Mexico that produce, formulate, or import pesticides for agricultural use (SAGARPA, 2011). United Mexican States Labor legislation requests companies to provide workers with education and job training for handling dangerous chemicals and the prevention of

Address for Correspondence: Betzabet Quintanilla-Vega, Departamento de Toxicología, CINVESTAV-IPN, Av. IPN #2508, Col. Zacatenco, México, D.F., 07360, México. Tel: (52) +55–5747-3800 Ext. 5446. Fax: (52) +55–5747-3395. E-mail: [email protected]

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Abbreviations: AChE, acetylcholinesterase; CPK, cell proliferation kinetics; CYP, cytochrome P450; FSH, follicular stimulating hormone; IUGR, intrauterine growth retardation; LH, luteinizing hormone;

LPO, lipid peroxidation; MDA, malondialdehyde; MN, micronuclei; OP, organophosphorous; PON1, human paraoxonase-1; ROS, reactive oxygen species; SCE, sister chromatid exchanges

occupational accidents, therefore, the employer has the responsibility for controlling the risks of occupational accidents (United Mexican States Constitution and Federal Labor Law). In addition, the Ministry of Health authorities, through COFEPRIS, specify additional provisions regarding the use of protective equipment and the value of safety practices during the field work and informative campaigns about the risk of pesticide use. Unfortunately, agriculture is still the lifestyle of rural communities, where peasants (campesinos) frequently own their fields (parcelas) and have no training on the risk of use of agrochemicals. COFEPRIS requests agrochemical companies to conduct toxicological studies to establish the maximum limit of pesticide residues in agricultural products to assure no adverse effects on human health according to World Health Organization, following the Good Practices of Laboratory from the Organization for Economic Co-operation and Development (OECD) guidelines. These studies include the evaluation of acute and long-term effects in animals (in two species, males and females) and on pesticide toxicokinetics (including metabolism). Additionally, to register any new chemical compound to be used in agriculture, companies must give information about proper pesticide management, personal protection equipment, signs and symptoms of intoxication, medical treatment and antidotes in case of intoxication, and toxicological category of pesticides. Likely, toxicological studies to evaluate the impact on the environment, including degradation index, concentration of residues in soil, plants and water and bioaccumulation, as well as effects on flora and fauna are also requested (INE, 2011). The current amount of pesticides used in the country is not available; however, data from some studies showed that OP pesticides are among the most used agrochemicals in Mexico, both in rural and urban communities, although their use varies according to the geographical area and type of crops. Due to the North American Free Trade Agreement (NAFTA) in 1994, pesticides from United States and Canada can be freely introduced to Mexico, a situation that represents a potential risk due to their high use. Epidemiological studies conducted in several regions of the country (North, Northeast, Pacific Coast, Centro, Southeast and South) have reported the use of OP in agriculture and floriculture at different patterns and frequencies; OP pesticides include methyl parathion, methamidophos, monocrotophos, diazinon,

chlorpyrifos, malathion, dimethoate, diclorvos and omethoate (Table 1). On the other hand, pesticide sales and use by urban sprayers have been barely studied in Mexico. There is only one study conducted in Nayarit State (Pacific Coast) reporting that urban sprayers mostly use OP (Fuentes et al. 2010), and that this group of pesticides is the most sold (52%) in that state (González-Arias et al. 2010). Most frequently used OP pesticides in the country belong to different toxic categories: methyl parathion (extremely toxic), methamidophos, monocrotophos, omethoate, dichlorvos and methyl oxydemeton (highly toxic), chlorpyrifos, diazinon and dimethoate (moderately toxic) and malathion (slightly toxic) (WHO, 2009). Some of these pesticides such as methyl parathion, methamidophos and omethoate have been banned or severely restricted (Rotterdam Convention, ANEX III, 2008), but unfortunately they are still used in rural and urban communities in Mexico (CICOPLAFEST, 2004). We believe that with a strict monitoring of the risk-benefit of pesticides use, Mexican health and environment authorities could actualize the current status of pesticide use and toxicity, since the last actualization of banned or restricted pesticides was made in 1991 (INE, 1991).

Organophosphorous pesticides OP pesticides are esters of phosphoric or thiophosphoric acids that are activated through an oxidative desulfuration by several enzymes of the cytochrome P450 (CYP) family to form the corresponding oxons (Jokanović, 2001), which are considered more toxic than their parent compounds. OP bioactivation has been reported in several rodent tissues, including liver, testis and brain (Albores et al. 2001; Soranno and Sultatos, 1992). The main deactivation pathway of polar metabolites (oxons) is through the paraoxonase-1 (PON1) enzyme to form the ultimate dialkylphosphates (DAP) that are easily eliminated in urine. Parent compounds can also be deactivated by glutathione conjugation through several isoforms of glutathione-S-transferase (GST) (Jokanović, 2001). Although the knowledge about the potential adverse health effects related to pesticide exposure in Mexican populations is limited, some studies have associated acute intoxications and chronic illness problems with pesticide exposure, and several factors increase the risk of toxicity, such as socioeconomic and educational issues, chronic exposure and the lack of safety practices Toxicology Mechanisms and Methods

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Organophosphorous pesticides research in Mexico 683 Table 1. Epidemiological studies conducted in Mexico related to the use and toxic effects of OP. Reference Geographical area/ population Type of OP Observations Fuentes et al. 2010 Nayarit State (W)/urban retailers, CP, MET, Me-Pa, DIM -Urban sprayers mostly use OP-Most González-Arias et al. 2010 n = 181 sold pesticides Martínez-Valenzuela et al. 2009 Sinaloa State (NW)/farmers, n = 70 MA, Me-Pa, DZN, MO -Profile of OP Schilmann et al. 2010 Morelos State (C)/Flower growing DZN, MET, OM, Me-Pa -Pesticide use pattern farmes, n = 88 Cortés-Genchi et al. 2008 Guerrero State (SW)/farmers, Not reported -Intoxication episodes n = 303 Sánchez-Guerra et al. 2009 Yucatan State (SE)/farmers, n = 80 MET, CP, Me-Pa, MA, -Intoxication episodes and more DZN than 10 symptoms Tinoco-Ojanguren and Chiapas State (S)/farmers, n = 65 Not reported -Intoxication symptoms-Low AChE Halperin, 1998 Rendón-von Osten et al. 2004 Campeche State (SE)/farmers, Me-Pa, MET, MO -Poisoning symptoms-Low AChE n = 127 Gamlin et al. 2006 Nayarit State (W)/working Not reported -Low AChE children*, n = 62 Rojas-García, et al. 2011 Nayarit State (W)/ urban retailers, CP, MET, Me-Pa, DIM -Low BChE n = 181 Blanco-Muñoz et al. 2010 Morelos State (C)/floriculturists, OM, MET, CP, MA OX -Decreased inhibin B and FSH n = 104 Recio et al. 2005, 2001, 2008 Durango State (N)/farmers, Me-Pa, MET, DIM, DZN -Decreased FSH and LH-Sperm n = 9-64 aneuploidies-Decreased semen quality Sánchez-Peña et al. 2004 Durango State (N)/farmers, n = 33 Me-Pa, MET, DIM, DZN -Altered sperm chromatin structure Gómez-Arroyo et al. 2000 Morelos State (C)/floriculturist DZN, Me-Pa, Et-Pa, -Increased frequency of MN and SCE women, n = 30 OM, DIC, MA, MET Martínez-Valenzuela et al. 2009 Sinaloa State (NW)/farmers, n = 70 MA, Me-Pa, DZN, MO -Increased frequency of MN and SCE Acosta-Maldonado Chihuahua State (N)/ CP, DZN, DIM, MA, MO, -Alterations in placenta maturity et al. 2007 pregnant women+, n = 371 Me-Pa Lacasaña et al. 2006 Morelos State (C)/agricultural MET, Me-Pa, CP, DIM -Increased risk of anencephalic child working mothers, n = 151 Moreno-Banda Morelos and Mexico States (C)/ DZN, MET, OM, Me-Pa -Increased risk of having a baby with low et al. 2009 floriculturist women, n = 264 birth weight in PON1 192RR mothers Pérez-Herrera et al. 2008 Yucatan State (SE)/ MET, CP, Me-Pa, MA, -Low sperm quality and sperm DNA farmers, n = 54 DZN damage in PON1 192 RR workers AChE, acetylcholinesterase; C, Centro; CP, chlorpyrifos; DIC, dichlorvos; DIM, dimethoate; DZN, diazinon; FSH, follicular stimulating hormone; IUGR, intrauterine growth retardation; LH, luteinizing hormone; MA, malathion; Me-Pa, methyl parathion; MET, methamidophos; MN, micronuclei; MO, monocrotophos; N, North; NW, Northwest; OM, omethoate; OX, methyl oxydemeton; S, South; SCE, Sister chromatid exchanges; SE, Southeast; W, West; *Working children on tobacco plantations; + Pregnant women living near agricultural communities.

including following instructions on how to apply pesticides, the use of personal protective equipment and the practice of washing their hands before eating after handling pesticides (Quintanilla-Vega et al. 2010). In Mexico, population is exposed to pesticides by their use in agriculture (open fields and greenhouses), in sanitary campaigns to eradicate infection diseases vectors, in urban pest control activities, including gardening, and during the manufacture, formulation or importation of pesticides; therefore, farmers and their families, people in their workplace and the general population by domestic use are at risk to their toxicity. Each scenario of pesticide exposure is complex and poorly documented in Mexico. In the next sections, data from published studies conducted in Mexico related to toxic effects or mechanisms of toxic action of OP pesticides are presented, and a few papers from outside for comparison. Authors made a search on existing literature and selected those papers that reported complete data, such as statistical values, © 2011 Informa Healthcare USA, Inc.

study design, subjects’ identification, exposure evaluation or treatment-dosing.

Neurological effects The most studied adverse effect of OP exposure is the inhibition of acetylcholinesterase (AChE) activity through phosphorylation of a serine residue in the active site (Gallo and Lawryk, 1991), causing intoxication episodes with severe cholinergic symptoms that may lead to death. There are few studies in Mexico reporting data on AChE inhibition, mostly in agricultural workers indicating the use of anti-cholinesterase pesticides (OP or carbamates) (Table 1). Tinoco-Ojanguren and Halperin (1998) conducted a longitudinal study in three rural communities from Chiapas State (Southern Mexico) in 65 peasants, before and after exposure to insecticides, and reported a significant lower AChE activity compared to the pre-exposure value or to a non-occupationallyexposed reference group. The lowest level of AChE was

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observed in residents of the poorest and most populated community with low educational level, who use the most toxic insecticides. While Rendón-von Osten et al. (2004) reported that farmers (n = 127) from four communities from Campeche State (Southeastern Mexico), who mainly used OP and carbamates, had significant lower AChE activity than a non-exposed group. Authors discuss the need for permanent information campaigns about the risks of pesticide use and the value of safety practices. On the other hand, Gamlin et al. (2006) evaluated AChE activity in a longitudinal study conducted in 62 children working on tobacco plantations during the harvest season in Nayarit State (Pacific Coast) and reported that 33% of the paired samples (during the harvest vs. 6–9 months after the harvest) had a depression on AChE activity of at least 15% (p