25 Pesticide Exposure and Health Related Issues in Male and Female Reproductive System Stavros Sifakis1, Mihalis Mparmpas1, Offie P. Soldin2 and Aristides Tsatsakis3 1Department of Obstetrics & Gynecology University of Crete, Heraklion, Greece 2Departments of Medicine, Oncology, Physiology and Obstetrics & Gynecology, PregnaTox, Georgetown University Medical Center, Washington D.C., 3Laboratory of Toxicology, Department of Medicine, University of Crete, Heraklion, 1,3Greece 2USA 1. Introduction During the last several decades there have been widespread uses of potent substances that, although effective in their intended use, have also been suspected of being harmful to reproductive health. This mixture of environmental contaminants that may adversely affect human fertility includes heavy metals (lead, mercury, arsenic), phthalates (plasticizers), bisphenol-A (building block of several plastics), polychlorinated biphenyls (lubricants), dioxins (byproducts of manufacture), pesticides and other agents. The impact of adverse effects on reproductive health include impaired gametogenesis, sperm maturation, decreased semen quality, miscarriages, ovulation and menstrual disturbances, infertility, stillbirths, developmental anomalies, cryptorchidism, hypospadias and cancer. The effects can be reversible, permanent or even transgenerational, take place in the offspring, as exposure can occur during pregnancy and intrauterine life, childhood or later. The route of exposure, dose, age, gender and genotype (susceptibility of the individual) are important factors that can determine the reproductive disorder. In this chapter we focus on the effects of exposure to pesticides during adulthood, on human male and female fertility, giving emphasis to semen quality and time to pregnancy. 2. Pesticides Pesticides are mainly utilized in agriculture for crop protection, often replacing the natural processes on which agricultural production had previously depended. Pesticides are also applied in homes and gardens. More than 140.000 tones of pesticides are used annually in the European Union for agricultural purposes only (Ramazzini, 2009). A pesticide is “any substance or mixture of substances intended for preventing, destroying or controlling any pest, including vectors of human or animal disease, unwanted species of plants or animals causing harm during or otherwise interfering with the production processing, storage, transport or marketing of food, agricultural commodities, wood and wood products or animal feedstuffs, or substances which may be administered to animals for the control of insects, arachnids or other pests in or on their bodies” (FAO, 2003). They www.intechopen.com 496 Pesticides - Formulations, Effects, Fate fall into three major classes: insecticides, fungicides, and herbicides, classification based upon the target organism. There are also rodenticides (for control of vertebrate pests), nematicides (to kill eelworms, etc), molluscicides (to kill slugs and snails), and acaricides (to kill mites) (Cox & Surgan, 2006). Pesticides may differ according to their chemical structure, their mechanism of action and the toxicity they exhibit, but typically each pesticide consists of one (or more) active ingredient, which exerts the pesticidal activity, and an inert ingredient, which is inactive and helps in handling the active ingredient. Several studies have shown that the inert ingredient is not as inactive as it was previously believed to be (Surgan, 2005; Cox & Surgan, 2006). Over 700 active ingredients are in use worldwide as pesticides, each with distinct chemical and toxicological properties (Toppari et al., 1996). Another classification categorizes pesticides according their chemical structure (Table 1). Insecticides include organochlorines, organophosphates, and carbamates. Organochlorine hydrocarbons (DDT, heptachlor) operate by disrupting the sodium/potassium balance of the nerve fiber. They are persistent in human tissue with the potential to bioaccumulate. Organophosphate (parathion, malathion) and carbamates (carbaryl, carbofuran) are less toxic and largely replaced organochlorines. They are inhibitors of acetylcholinesterase, causing paralysis. Common herbicides include pheoxy and benzoic acid herbicides (2,4-D) and triazines (atrazine). Fungicides (vinclozolin, mancozeb) have sulfur as the most common active ingredient. Nicotinoids and pyrethroids are plant-derived pesticides (fenvalerate, pyrethrin). In addition to the desired effects of crop protection and pest management, pesticides have some recognized adverse impacts on human health and the environment. Humans have a great risk of exposure through several pathways in occupational, agricultural and household use. Inhalation, oral, dermal and ocular, are four possible routes for pesticide exposure. Ingestion of food and water is thought to be the main routes of pesticide exposure in the general population, while dermal absorption is suspected to be the main source of occupational exposure (Toppari et al., 1996). Over 25% of fruits, vegetables, and cereals are known to contain detectable residues of at least two pesticides and more than 300 different pesticides are known to contaminate food products sold in the EU (Ramazzini, 2009). In the majority of cases, however, human exposure is unintentional and unintended (Ribas-Fitó, 2002). Pesticides are accused of causing short-term adverse health effects. Acute health effects include stinging eyes, rashes, blisters, blindness, nausea, dizziness, diarrhea and death (Jeyaratnam, 1990; Sanborn et al., 2007). They are suspected also for a wide range of chronic effects, which can occur months or years after the exposure, such as cancers, neurological and developmental toxicity, immunotoxicity, genotoxicity, respiratory effects and disruption of the endocrine system. Pesticides may affect not only the exposed individual but also subsequent generations (Alavanja et al., 2004; Ritter et al., 2006; McCauley et al., 2006; Bassil et al., 2007). There has been rising concern in many developed countries about the adverse effects of pesticides on human reproduction, ranging from female and male subfertility to abortion, stillbirths, birth defects and malformations (García, 2003; Weselak et al., 2007; Peiris-John & Wickremasinghe, 2008). They may cause reproductive toxicity with direct damage to the structure of the cells or as a result of biotransformation into metabolites, or interference with processes necessary for the natural homeostasis and equilibrium. They may act like hormones in the endocrine system and disrupt the function of the natural endogenous hormones, when doing so they are often called endocrine disrupting chemicals (EDC) (Lathers, 2002; Diamanti-Kandarakis et al., 2009). This group of compounds identified as EDC is heterogeneous and includes synthetic or natural chemicals. www.intechopen.com Pesticide Exposure and Health Related Issues in Male and Female Reproductive System 497 organochlorides DDD, DDT, DDE, chlordane, kepone, dieldrin, endosulfan, heptachlor, lindane, mirex, methoxychlor, toxaphene organophosphorus chlorpyrifos, glyphosate, diazinon, dimethoate, malathion, methamidophos, parathion, terbufos, tribufos, trichlorfon carbamates aldicarb, carbaryl, carbofuran, fenoxycarb, propoxur pyrethroids cypermethrin, fenvalerate, permethrin, pyrethrin, pyrethrum, resmethrin, tetramethrin anilides/anilines metolachlor, pretilachlor, propachlor, trifluralin phenoxy 2,4-D, 2,4-DB , 2,4,5-T, MCPA, MCPB , fenoprop triazines atrazine, cyanazine, hexazinone, prometryn, propazine, simazine, terbutryn quaternary diquat, MPP, paraquat ureas chlortoluron, DCMU, metsulfuron-methyl, monolinuron others acetamiprid, amitraz, chlordimeform, cyromazine, diflubenzuron, nithiazine, sulfuramid, thiachloprid, xanthone Table 1. Classification of pesticides based on their chemical structure. 3. Pesticides as Endocrine Disrupting Chemicals (EDC) Pesticides may act as endocrine disruptors and alter the hormonal homeostasis in both males and females and lead to subfertility. The term “endocrine disruptors” was introduced into literature with an article published in 1993 (Colborn, 1993). An endocrine disruptor was defined by the U.S. Environmental Protection Agency (EPA) as “an exogenous agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for the maintenance of homeostasis, reproduction and developmental process” (Kavlock et al., 1996). The group of EDC includes pesticides and various synthetic substances such as polychlorinated biphenils (PCB), polybrominated biphenyls (PBB), bisphenol-A (BPA), phthalates and dioxins natural compounds such as phytoestrogens (Fourth National Report on Human Exposure to Environmental Chemicals, 2009) are used as solvents, lubricants, plasticizers, cosmetics etc. They are usually small molecules (mass 1000 Daltons) and often have a phenolic moiety that probably mimics natural steroid hormones (Diamanti-Kandarakis et al., 2009). They contain chlorine or other halogens (bromine, iodine or fluorine) with strong interaction and so they resist degradation. They usually have a long half-life and accumulate in the environment, sometimes remotely from the place they were produced. Substances banned even decades ago can still be found in the environment and in living organisms. In humans and animals EDCs are stored in fatty tissue or they may be metabolized into more toxic compounds. The predominant sources of exposure are food, water and air. The routes of exposure include ingestion, inhalation and dermal absorption. www.intechopen.com 498 Pesticides - Formulations, Effects, Fate Natural hormones act in very low concentrations, similarly, can elicit adverse effects in low doses. Occasionally, the EDCs do not follow the classic dose-response effect and low doses may result in stronger effects than high doses (vom Saal et al., 2009). Humans are exposed concomitantly to a large number of compounds. These substances may enhance and have a synergistic or antagonistic effect, and as cited above, some substances can be metabolized in more toxic products (Crews et al., 2003). One of the reasons of the difficulty studying the damage after exposure to a single agent is this mixture of compounds which is accumulated in human organisms. An issue of critical importance is the timing of exposure, since damage is age sensitive. The same dose can have different effects in fetuses, newborn, infants or adults. Given the same doses, a developing organism (embryo, neonate) whose growth is highly controlled by the endocrine system is more vulnerable to EDCs, than an adult (Guo et al., 1995; Bigsby et al., 1999; Lilienthal et al., 2006). The damage incurred by the exposure may not be immediate and may only be manifested in adulthood or during aging. The consequences may be apparent even in subsequent generations and the classic example is the cases of vaginal carcinoma in daughters of mothers who were exposed to DES during their pregnancies (Herbst et al., 1999; Anway & Skinner, 2006; Rubin, 2007). The susceptibility of an individual may vary due to genetic polymorphism and so the results of the same exposure could be different. Initially it was thought that ECDs act via nuclear hormone receptors (e.g. estrogen, progesterone, androgen, thyroid receptors), but now it is believed that they act also via membrane, non-steroid receptors (e.g. dopamine, serotonin, nor-epinephrine receptors). Catecholamine hormones following synthesis are stored in granular vesicles intracellularly. Steroid hormones are not stored but readily synthesized following gonadotropin stimulation of the gonads and are usually found in the circulation bound by carrier proteins (only free hormones are biologically active). Once reaching their tissue targets steroid hormones exert their action by binding to different kinds of nuclear receptors. Explicit hormones bind specific receptors and individualized mechanisms follow by intracellular signalling (e.g. protein kinase–C activation or phosphatidylinositol turnover). Hormones are mostly catabolised in the liver. Consequently, EDCs can participate in most aforementioned pathways thereby changing hormone synthesis patterns, mimicing hormone function or blocking it by occupying the receptor site, modulating the number of the receptors and their affinities for specific molecules and altering hormone clearance (Gore et al., 2006; Gore, 2007; Gore, 2008). Sex hormones synthesis is regulated by the hypothalamic-pituitary-gonadal axis. LH and FSH are synthesized by the anterior pituitary under the influence of pulsatile secretion of GnRH, released by the hypothalamus. Several pesticides have been reported to act as estrogen agonists, e.g. methoxychlor, endosulfan, toxaphene, kepone, DDT, fenarimol, alachlor, pentachrophenol, fenvalerate, chlordecone (Soto et al., 1995; Cummings & Gray, 1997; Garey & Wolff, 1998; Andersen et al., 2002; Kojima et al., 2004). On the other hand, other pesticides such as vinclozolin, p,p- DDE and o,p-DDT may have anti-androgenic activity, or both estrogenic and antiandrogenic activity (Kelce et al., 1994; Kelce et al., 1995; Kelce & Wilson, 1999). The fungicide methyl-2-benzimidazole carbamate decreases estradiol production in primary cultures of human ovarian granulosa (Can & Albertini, 1997). Treatment of rats with heptachlor suppresses progesterone and estradiol concentrations in blood (Oduma et al., 2006). Progesterone concentrations also decrease during early pregnancy in the rabbit following exposure to the pesticide DDT (Lindenau et al., 1994). DDT was found to be www.intechopen.com Pesticide Exposure and Health Related Issues in Male and Female Reproductive System 499 estrogenic, but its major metabolite DDE, has considerable antiandrogenic activity (Kelce et al., 1995). Further, atrazine seems to have estrogenic and antiandrogenic properties and was suggested to reduce testicular testosterone in male rats exposed to it (Stoker et al., 2000). Lindane intercalates into the sperm membrane and may inhibit sperm responsiveness to progesterone in vitro (Silvestroni & Palleschi, 1999). Lindane also inhibits steroidogenesis by reducing StAR (steroidogenic acute regulatory) protein-mediated cholesterol transfer (Walsh & Stocco, 2000). Neonatal exposure to either DES or flutamide also inhibited steroidogenesis and StAR protein expression in the fetal rat Leydig cell (Mikkilä et al., 2006). This protein mediates cholesterol passage through mitochondrial membranes and impaired expression results in decreased testosterone production in vitro (Manna et al., 2001). Testosterone concentration is also reduced with azole fungicides (ketoconazole) due to impaired enzymatic activity of 17α–hydroxylase and 17,20-lyase (Wang et al., 1992; Bahshwan et al., 1998; Taxvig et al., 2008). In rats, fenarimol, a different fungicide, was found to cause a dose-related decrease in fertility (Hirsch et al., 1986). In vitro studies of some pesticides such as fenarimol, prochloraz, imazalil and dicofol, indicate these pesticides inhibit the conversion of androgens to estrogens through CYP 19 aromatase inhibition (Vinggaard et al., 2000). Rats treated with mancozeb demonstrate a decrease in the number of healthy follicles and an increase in the number of atretic follicles (Mahadevaswami et al., 2000). EDCs have also been associated with breast cancer, PCO and endometriosis in women, cryptorchidism, hypospadias, testicular and prostate cancer in men, alteration in pituitary and thyroid gland functions (Crisp et al., 1998; Bretveld et al., 2006; Diamanti- Kandarakis et al., 2009). 4. Pesticides and semen quality Approximately 6% of adult males are thought to be infertile (Purvis & Christiansen, 1992). Male factors are responsible for at least 20% of cases of infertility. Male infertility is related to impaired semen quality and may be due to a variety of causes including genetic (Klinefelter’s syndrome), congenital (cryptorchidism), endocrine (hypogonadism), obstructive (vasectomy), infective (chlamydia), vascular (varicocele), neoplastic (carcinoma of the testis), lifestyle, and environmental (heat, drugs, pesticides, irradiation) factors. Others causes include sexual dysfunction related to erection and ejaculation (Purvis & Christiansen, 1992; Dohle et al., 2005). However, in many cases male infertility is regarded as idiopathic (40-75%), and no cause can be identified. Semen analysis is used to evaluate semen quality, which is taken as a surrogate measure of male infertility. The World Health Organization has provided reference values for human semen characteristics (Cooper et al., 2010). There is evidence of regional variation in semen quality that may be an expression of gene polymorphisms, different climate, lifestyle and exposure to magnetic fields or chemical substances such as pesticides (Mallidis et al., 1991; Jørgensen et al., 2001; Swan et al., 2003; Li et al., 2010). Seasonal variation has also been detected (decrease of sperm density and total sperm count during summer) (Levine, 1999; Krause & Krause, 2002). These factors, together with the variability in techniques and methodologies used, are reasons for some controversial results in studies that analyze semen quality changes overtime. Thus, the issue of a decline in semen quality overtime is equivocal. Following the publication of the meta- analysis conducted by Carlsen et al. in 1992, demonstrating a decline in human semen quality over the last 50 years (mean sperm count from 113 millions/ml in 1940 to 66 www.intechopen.com 500 Pesticides - Formulations, Effects, Fate millions/ml in 1990), numerous related studies have been published. Studies by Swan et al. had consistent results with those of Carlsen et al. (1992) and supported that historical data on sperm density, despite large random error, are reliable (Swan et al., 1997; Swan & Elkin, 1999; Swan et al., 2000). However, Olsen et al. (1995) reanalyzed the data used in a linear model to predict sperm quality deterioration in the last 50 years, advocate that the data are only robust during the last 20 years (1975-1995), in which other statistical models (quadratic, spline fit and stairstep), except the linear model, suggest constant or slightly increasing sperm counts. Studies from Italy, Denmark, Canada, Tunisia, India, Poland, Israel, Scotland, Greece and Germany suggest that there has been a decline, or sperm parameters are impaired in young populations (Adamopoulos et al., 1996; Younglai et al., 1998; Bilotta et al., 1999; Almagor et al., 2003; Vicari et al., 2003; Jørgensen et al., 2006; Sripada et al, 2007; Adiga et al., 2008; Paasch et al, 2008; Horak et al., 2008; Feki et al., 2009). Conversely, other reports from US, Japan, Korea, Sweden, Spain, Israel and Czech Republic showed no significant evidence of deterioration in sperm quality (Fisch et al., 1996; Paulsen et al., 1996; Benshushan et al., 1997; Berling & Wölner-Hanssen, 1997; Andolz et al., 1999; Seo et al., 2000; Itoh et al., 2001; Zvĕrina et al., 2002). The materials and methods of the studies mentioned varied widely, as well as time period (one, two, or more decades), population sample (e.g. individuals in infertile relationship or fertile subjects who participated voluntarily) and the level of pollution in the various geographical regions. Merzenich et al. (2010) conclude that former meta-analyses of sperm count data show a global downward trend, but this conclusion should be interpreted with caution, because the included studies are of great heterogeneity. The geographic variation in semen quality may reflect different exposures to endocrine disruptors, such as pesticides (Swan, 2006). Pesticides might have the ability to interrupt male fertility at several different sites in the reproductive pathway and by one or more mechanisms, as cited previously. Thus, they can interfere with the hypothalamopituitary axis that regulates, through the production of the gonadotrophins FSH and LH, the function of Sertoli and Leydig cells, impairing spermatogenesis and steroidogenesis. Tables 2a,b,c lists the studies published evaluating the association between exposure to pesticides and human sperm quality. Literature reviews and articles investigating chemical compounds, without including pesticides, were excluded. Studies evaluating pregnancy outcomes and no sperm quality were excluded too. Sperm quality was assessed evaluating conventional parameters (concentration, motility, morphology) or sperm DNA/chromatin integrity and aneuploidy. Sixty-three reports, satisfying these criteria were identified and included in Tables 2a,b,c. Among them six (6/63) studies evaluated the recovery of sperm quality, years after cessation of exposure to DBCP (5) and kepone (1). Thirty-six (36/63) studies examined exposure to single, specific pesticides or metabolites and included DBCP, DDT, DDE, EPB, 2,4-D, kepone (chlordecone), molinate, carbaryl, fenvalerate, ethylparathion, methamidophos, 1N (metabolite of carbaryl and naphthalene), TCPY (metabolite of chlorpyrifos and chlorpyrifos-methyl) and 3PBA, CDCCA, TDCCA (pyrethroid metabolites). The majority of the pesticides cited above are now banned or severely restricted, at least in USA or EU. Twenty-one (21/63) studies evaluated mixture of compounds such as fungicides, insecticides or herbicides with or without specifying the exact pesticides. Some of the pesticides involved in these studies are: alachlor, diazinon, acetochlor, malathion, atrazine, metolachlor, DEET (insect repellent), 2,4-D, aldicarb and cadusaphos, ethoprothos, isazophos, terbufos, pyrimiphos-ethyl (organophosphorus pesticides). www.intechopen.com Pesticide Exposure and Health Related Issues in Male and Female Reproductive System 501 4.1 Studies with little or no evidence of an association Eighteen studies of the 63 (18/63) found no or little evidence of association between pesticide exposure and sperm quality (Table 2a). Eight studies (8/18) involved a mixture of compounds and ten (10/18) single pesticides. Carbaryl and molinate were reported in one study each. Ten studies (10/18) were related to DDT and metabolites most of the times p,p’- DDE, the known persistent pesticide banned many years ago (not all over the world). Two of the ten studies evaluated DDT in mixtures and eight as a single pesticide. Five (5/10) of the reports that found no or little association between DDT, DDE and semen quality were carried out by the INUENDO project (including the two substudies of INUENDO by Rignell-Hydbom et al. (2004 & 2005). INUENDO (INUit-ENDOcrine) is the acronym for “Biopersistent organochlorines in diet and human fertility. Epidemiological studies in time to pregnancy and semen quality in Inuit and European populations”. This EU project (2002- 2005) used serum levels of CB-153 (polychlorinated biphenyl) and p,p’-DDE, the main DDT metabolite, to estimate the impact in human fertility in epidemiological studies including Inuits from Greenland and Caucasians from Poland, Sweden and Ukraine. Hauser et al. (2003) conducted two cross sectional studies and found a limited evidence of an inverse association between p,p-DDE and sperm motility as well as no strong relationships between the levels of this compound and sperm DNA damage. Furthermore, Charlier et al. (2005) estimated serum and seminal plasma concentrations of p,p-DDE in fertile and sub or infertile young men. Blood concentrations of p,p’-DDE were very low in both groups. No p,p’-DDE detected in seminal plasma of either groups. Of note, the mothers of the exposed subfertile men had serum level of p,p’-DDE significantly higher than the mothers of the control group. Two studies did not evaluate DDT exposure separately, but it was included in a sum of other compounds. Magnusdottir et al. (2005) concluded that poor semen quality is associated with sedentary work and obesity but not with plasma levels of fourteen organochlorine pesticides including DDT and metabolites. Weiss et al. (2006) evaluating exposure, in Germany and in Tanzania, to a mixture of PCBs and pesticides, including DDT, found these pesticides had no impact on sperm quality. However high serum concentrations of DDT-DDE were associated with lower pregnancy rates in Germany. Two out of the eighteen reports that showed little or no association between pesticide exposure and semen quality were performed by ASCLEPIOS (Larsen et al., 1998a; Härkönen et al., 1999). It was an EU project (1993-1998), that was carried out in 14 European centers and focused on occupational exposure to the fungicides styrene and inorganic lead. Questionnaire studies of time to pregnancy were combined with longitudinal and cross sectional studies of semen quality. Tielemans et al. (1999a) conducted a case-control study and found no associations between exposure to pesticides and poor semen quality, but few subjects were exposed to pesticides (the rest of the sample was exposed to chemical pollutants different from pesticides, such as solvents and metals). Juhler et al. (1999) found similar results indicating minor association, comparing traditional and organic farmers, but for all the groups of exposure the average dietary intake of pesticides was low. Smith et al. (2004) found no significant differences in sperm aneuploidy or diploidy frequencies between men exposed to a mixture of pesticides and control groups, but the sample was rather small (n=20+20). In a cross-sectional study conducted by Multigner et al. (2008) semen characteristics were evaluated in association to exposure to a mixture of organophosphorus pesticides (cadusaphos, ethoprothos, isazophos, terbufos, pyrimiphos-ethyl and one carbamate the aldicarb). No significant difference was www.intechopen.com 502 Pesticides - Formulations, Effects, Fate found between exposed and unexposed workers (in banana plantations), but exposure was assessed by a questionnaire and not by chemical analysis. Tomenson et al. (1999) conducted a longitudinal study and found no evidence that sperm and serum hormones levels were related to molinate exposure (thiocarbamate herbicide). Whorton et al. (1979) found no apparent effects on sperm count in workers exposed to carbaryl, but three subsequent relative studies indicated contrary results. Authors & Year Study Pesticide N Country Type Whorton et al, 1979 carbaryl 47 workers CS (USA) Larsen et al, 1998a 248 farmers users or not users of (ASCLEPIOS) Mixture L pesticides during a spraying season (Denmark) Härkönen et al, 30 healthy farmers before and after 1999 (ASCLEPIOS) fungicides CS exposure (Finland) molinate Tomenson et al, (thiocarbamate 272 workers at three US plants. L 1999 (UK) herbicide) Tielemans et al, Occupational Male partners of couples having 1999a exposures (solvents, their first consultation in two CC (The Netherlands) metals, pesticides) infertility clinics (n=899) Juhler et al, 1999 171 traditional and 85 organic mixture CC (Denmark) farmers. Hauser et al, 2003a 212 male partners of subfertile DDT, DDE, PCBs CS (USA) couples Hauser et al, 2003b 212 male partners of subfertile DDT, DDE, PCBs CS (USA) couples Rignell-Hydbom et CB-153 195 Swedish fishermen aged 24-65 CS al, 2004, (Sweden) p,p ’-DDE Smith 2004 et al, mixture 20 exposed, 20 non exposed CC (Canada) 73 fertile young men (controls) & 23 Charlier 2005 et al, p,p’-DDE mothers; 82 sub or infertile young CC (Belgium) men (cases) & 19 mothers 25 poor semen quality, 20 normal Magnusdottir 2005 PCBs, organochlorine semen quality & idiopathic CS et al, (Iceland) pesticides, (p,p’DDE) subfertility, 27 normal semen quality & female subfertility Rignell-Hydbom et CB-153 176 Swedish fishermen CS al, 2005 (Sweden) p,p’-DDE (low & high intake of fatty fish) 193 Inuits – Greenland; 178 Swedish Spano 2005 et al, CB-153 fishermen; 141 men from Poland; CS INUENDO, (Italy) p,p’-DDE 195 men from Ukraine www.intechopen.com Pesticide Exposure and Health Related Issues in Male and Female Reproductive System 503 200 Inuits –Greenland; 166 men Stronati et al, 2006, CB-153 from Sweden; 134 men from Poland; CS INUENDO, (Italy) p,p’-DDE 152 men from Ukraine Toft et al, 2006, 194 men from Greenland; 185 men CB-153 INUENDO, from Sweden; 189 men from Poland; CS p,p’-DDE (Denmark) 195 men from Ukraine mixture of PCBs & Weiss et al, 2006 31 women, 16 men from Tanzania, pesticides including CS (Germany) 21 couples from Germany DDT,DDE organophosphorus 42 exposed & 45 non exposed in Multinger et al, pesticides and one banana plantations in Guadeloupe CS 2007 (France) carbamate (parallel assessment in wild rats) Table 2a. Studies evaluating the association between exposure to pesticides and human sperm quality. Studies with no or little evidence of an association; 2b: Studies with evidence of an association; 2c: Studies evaluating the recovery of sperm quality (CS: cross sectional study; CC: case-control study; L: longitudinal study; R: retrospective study; P: pilot study). 4.2 Studies with evidence of an association Thirty-nine (39/63) studies that varied widely in materials, methods, exposure and assessment of exposure concluded that there was evidence of an association between exposure to pesticides and impaired semen quality. Twenty-six (26/39) studies evaluated exposure to single pesticides or metabolites and thirteen (13/39) studies evaluated exposure to mixtures of compounds including pesticides or mixtures of pesticides. Evidence of an association was found in studies involving: - DDT and DDE: Only in six of the 16 studies overall involved, five as a single pesticide and one in a mixture. - DBCP: All studies showed evidence of impairment. Thrupp in his article examined a remarkable case of massive sterilization of approximately 1500 workers exposed in banana plantations in Costa Rica (Thrupp, 1991). Slutsky et al. in his report which represents the largest cohort of DBCP exposed workers, found that after a median exposure of three years, 64.3% of these men overall, and 90.1% of men studied from the Philippines, had oligospermia or azoospermia (1999). Whorton et al. (1977), Potashnik et al. (1978), Lipshultz et al. (1980) and Egnatz et al. (1980) had the same results of a significant association. There are five studies more involving DBCP, but related to sperm recovery after cessation of exposure and are cited in the related paragraph. - EPB: One cross-sectional and one longitudinal study with small sample size. - Kepone: A cross-sectional study measuring blood levels found oligospermia and decreased sperm motility. One more study involving kepone was related to the recovery of sperm after exposure and is cited in the related paragraph. - 2,4-D: One cross sectional study evaluated exposure using urine samples and observed asthenospermia, teratospermia and necrospermia. The second study evaluated this compound in a mixture of eight pesticides and found relation with poor semen quality. - Fenvalerate: All studies conducted in China; three of them reporting impairment of conventional parameters of sperm quality and one increased percentage of sperm aneuploidy and altered morphology. www.intechopen.com 504 Pesticides - Formulations, Effects, Fate - Carbaryl: The first, a cross-sectional study, showed increase in abnormal morphology, the second study found altered seminal volume and sperm motility and the third study showed increased frequencies of aneuploidy. - Ethylparathion and Methamidophos: Semen and urine samples were collected in order to estimate exposure to these organophosphate pesticides. There was a decrease in sperm concentration and motility but no significant difference was found in sperm morphology. - 1N and TCPY: The first compound is a metabolite of carbaryl and naphthalene and the second a metabolite of chlorpyrifos and chlorpyrifos-methyl. This study used biological markers of exposure (urine analyses for metabolites) and several modeling approaches to test the robustness of the data. Statistically significant inverse dose- response relationships between 1N and sperm concentration and motility were found. There was a suggestive association between TCPY and sperm concentration and motility. Sperm morphology was not significantly associated with both 1N and TPCY. Only a single urine sample collected to estimate exposure and only a single semen sample collected to assess semen quality. - 3PBA: It is the main metabolite of pyrethroids such as cypermethrin, deltamethrin, permethrin with high detection rate in the general population. The first study with rather large sample size showed suggestive association between increased urinary 3- PBA concentration (creatinine adjusted) and sperm concentration. There was an association between straight line velocity and curvilinear velocity (sperm progression and motion parameters) with urinary 3-PBA concentration (creatinine adjusted), while sperm volume, sperm number per ejaculum and sperm motility were weakly or not significantly associated. A second study that evaluated two more pyrethroid metabolites, CDCCA and TDCCA, was similar in design and found evidence for reduced semen quality and increased DNA damage related to the urine pyrethroid metabolites. Swan et al. (2003b) evaluated exposure to a mixture of eight pesticides in two different populations within Missouri and Minnesota. The small sample size limited statistical power. Exposure was assessed by urine analysis. Study concluded that Alachlor, atrazine, 2,4-D, metolachlor and a diazinon metabolite were associated with poor semen quality in Missouri. However, no significant associations were found for acetochlor, DEET and malathion dicarboxylic acid. Within Minnesota, the levels of pesticides were low for any of the pesticides, no significant associations were found too, but because of the overall results this study is classified in this category. Dalvie et al. (2004) evaluated exposure to DDT in workers in South Africa, in relation to sperm quality and sexual function. Exposure was assessed by serum levels of o’p’ and p’p’ isomers of DDT, DDE, DDD. Sperm count and density were in the normal range. 84% of morphology scores were below the WHO criteria and p’p’DDT was negatively associated with sperm count (after correction for age, abstinence, physical abnormality and fever). Although no strong evidence for a DDT overall effect in sexual function and reproductive outcomes was found semen quality was impaired resulting in this study being cited in this category. Dallinga et al. (2002) studied a group of men with poor semen quality vs. group of men with normal, based on the progressive motility of sperm. Blood samples were collected in order to determine whether differences in sperm quality were related with differences in serum concentrations of organochlorines, including DDT. No significant differences in www.intechopen.com