**7. Studies on DDT toxicity**

Despite the concerns of DDT opponents (see par. 6.1), to date there is no consistent evidence that DDT or its metabolite DDE can be toxic for humans. Indeed, despite the large number of studies performed in this context, results are highly contradicting, probably due to differ‐ ent analytical conditions and approaches used by different researchers. On the other hand, DDT toxic effects on animals have been demonstrated quite convincingly. This should be taken in account in the context of general environmental issues (par. 5.5) which led to DDT ban in malaria-free countries. In the following sub-sections, current knowledge on DDT ef‐ fects on animal and human health will be reviewed.

#### **7.1. Animals**

DDT satisfied even the most basic epidemiological criteria to prove a cause-and-effect rela‐

According to Bouwman et al. (Bouwman et al., 2011), "the centrist-DDT point of view adopts an approach that pragmatically accepts the current need for DDT to combat malaria transmission using indoor residual spraying (IRS) but at the same time recognizes the risks inherent in using a toxic chemical in the immediate residential environment of millions of people". Thus, scientists sharing a centrist-DDT point of view such as Bouwman and collea‐ gues suggest caution in using DDT because of insufficient investigation whether DDT is safe or not; however, they do recognize its undoubted benefits in areas endemic for malaria and its major role as a life-saving tool. In this context, DDT-centrists call for alternative chemi‐ cals, products, and strategies, eventually in order to terminate in the future any use of DDT in IRS for malaria control. As it will be discussed in paragraph 6, some vector control meth‐ ods are already available as alternatives to DDT. Two of these, the use of alternative insecti‐ cides in IRS and the use of insecticide-treated bed nets (ITNs), are mainstreamed because of their proven impact on the malaria burden; other alternatives are receiving limited attention

DDT supporters consider DDT safe to use in IRS when applied correctly, and promote DDT to be used for IRS in malaria control where it is still effective. In their perspective, in a riskbenefit comparison, the eventual toxic effects of DDT would be far less than those caused by malaria (Africa Fighting Malaria, 2010; Roberts et al., 1997). Apparently, this is the point of view of WHO itself, since it approved in 2006 the use of DDT, particularly indoor residual spraying of walls, in areas endemic for malaria for health-related reasons (WHO, 2006a; WHO, 2006b), although it also carefully drew up major guidelines (WHO 2000). Moreover, several national malaria control programs and ministers of health repeatedly proclaimed the importance of DDT for disease control programs in countries with high incidence of malar‐ ia. These include Namibia and the Southern African Development Community (SADC), which recently reasserted that DDT is a major tool for malaria vector control and announced their intention to produce DDT locally (SADC, 2011). Similarly, the 35 heads of state of the countries members of the African Leaders Malaria Alliance (ALMA) recently endorsed use of DDT in indoor residual spraying (IRS) (ALMA 2010). As a matter of fact, as a conse‐ quence of the global eradication program recently launched by charity foundations, which invested relevant amounts of money in DDT-based vector control (Roberts & Enserink, 2007; Greenwood, 2008; Khadjavi et al., 2010; Prato et al., 2012), in 2010 World Health Organiza‐ tion (WHO) officially registered - for the first time in the last decade - a decline in estimated malaria cases and deaths, with 655.000 deaths counted among more than 200 million clinical

to date, but may play an important role in the future (van den Berg, 2009).

tionship (Tren & Roberts, 2011).

342 Insecticides - Development of Safer and More Effective Technologies

**6.2. Centrist-DDT point of view**

**6.3. Pro-DDT point of view**

cases worldwide (WHO 2011a).

Due to its lipophilicity, DDT readily binds with fatty tissue in any living organism, and be‐ cause of its chemical stability, bioconcentrates and biomagnifies with accumulation of DDT through the food chain, in particular in predatory animals at the top of the ecological pyra‐ mid (Jensen et al., 1969). By the mid 1950s, experimental studies on animals have demon‐ strated chronic effects on the nervous system, liver, kidneys, and immune systems in experimental animals attributable to DDT and DDE (Turusov et al., 2002), and it quickly be‐ came apparent that this could extend to the broader environment (Ramade, 1987). However, dose levels at which effects were observed are at very much higher levels than those which may be typically encountered in humans.

DDT is highly toxic to fish. The 96-hour LC50 (the concentration at which 50% of a test pop‐ ulation die) ranges from 1.5 mg/litre for the largemouth bass to 56 mg/litre for guppy. Small‐ er fish are more susceptible than larger ones of the same species. An increase in temperature decreases the toxicity of DDT to fish (PAN, 2012).

DDT and its metabolites can lower the reproductive rate of birds by causing eggshell thin‐ ning which leads to egg breakage, causing embryo deaths. Sensitivity to DDT varies consid‐ erably according to species. Predatory birds and fish-eating birds at the top of the food chain are the most sensitive. The thickness of eggshells in peregrine falcons was found to have de‐ creased dramatically following the pesticide's introduction (Ratcliffe, 1970), likely due to hormonal effects and changes in calcium metabolism (Peakall, 1969). Colonies of brown peli‐ cans in southern California plummeted from 3000 breeding pairs in 1960 to only 300 pairs and 5 viable chicks in 1969. In the US, the bald eagle nearly became extinct because of envi‐ ronmental exposure to DDT. According to research by the World Wildlife Fund and the US EPA, birds in remote locations can be affected by DDT contamination. Albatross in the Mid‐ way islands of the mid-Pacific Ocean show classic signs of exposure to OCs chemicals, in‐ cluding deformed embryos, eggshell thinning and a 3% reduction in nest productivity. Researchers found levels of DDT in adults, chicks and eggs nearly as high as levels found in bald eagles from the North American Great Lakes (PAN, 1996).

## *7.1.1. Reproductive and teratogenic effects (birth defects)*

DDT causes adverse reproductive and teratogenic effects in test animals. In one rat study, oral doses of 7.5 mg/kg/day for 36 weeks resulted in sterility. In rabbits, doses of 1 mg/kg/day administered on gestation days 4-7 resulted in decreased foetal weights. In mice, doses of 1.67 mg/kg/day resulted in decreased embryo implantation and irregularities in the oestrus cycle over 28 weeks (Agency for Toxic Substances and Disease Registry, 1994). Many of these observations may be the result of disruptions to the endocrine (hormonal) system.

Much of the epidemiologic research about the possible influence of pesticide exposure in general on pregnancy outcome suffers from significant methodological problems. The larg‐ est and most rigorous study of DDT and adverse reproductive outcomes was conducted in a US perinatal cohort of over 44,000 children born between 1959 and 1966 (Longnecker et al., 2001). DDE concentration was estimated in stored serum taken during pregnancy from mothers of 2380 children. Increasing concentrations of serum DDE were statistically and sig‐ nificantly related to preterm births, intra-uterine growth retardation (Siddiqui et al., 2003) and maternal diastolic blood pressure (Siddiqui et al., 2002). On the other hand, other stud‐ ies have failed to find any relationship between maternal DDT exposure and birth weight

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345

Both animal models and early human studies have suggested a link with exposure to the DDT and the most common adverse pregnancy outcome (spontaneous abortion) (Saxena et al., 1980). However, the results of recent research are inconsistent. One small case-control study nested in a longitudinal study of Chinese textile workers found significantly higher levels of DDE in women with spontaneous abortion than full term controls. (Korrick et al., 2001) On the other hand, other studies have been unable to find an association (Gerhard et al., 1998). Unclear findings have been identified about the impact of DDT on fertility (Cohn et al., 2003): the probability of daughters' pregnancy fell with increasing levels of DDT in maternal serum, but it increased with increasing levels of DDE. Finally, OCs appear to trans‐ fer freely across the placenta from mother to foetus and could be also excreted in human

In the late 1960s, concentrations of DDE in animals and first-trimester human fetal tissues correlated with reproductive abnormalities in male offspring such as hypospadias and un‐ descended testes (Gray et al., 2001). A case-control study nested in a US birth cohort (1959– 1966) (Longnecker et al., 2002) showed small increases in crypt-orchidism, hypospadias, and polythelia among boys with the highest DDE maternal serum levels when compared with those with the lowest maternal levels, although none of these were statistically significant. On the other hand, other studies failed to find a significant association between influence of DDT exposure on hormone levels in adult men, or DDT levels and sperm concentration/

Bone mineral density, which is regulated by the antagonistic effect of androgens and oestro‐ gens, may be another possible target of endocrine disruption. DDT has been shown to mod‐ ulate trophoblast calcium handling functions *in vitro* (Derfoul et al., 2003) and two small cross-sectional studies have suggested there may be a weak association between serum DDE levels and reduced bone mineral density (Beard et al., 2000; Glynn et al., 2000). However, a

*In vitro* studies suggest that DDT and its metabolites do not influence thyroid metabolism (Langer et al., 2003; Rathore et al., 2002). Other research has failed to find a significant associa‐ tion with endometriosis, a hormone dependant pelvic inflammatory disease (Lebel et al., 1998).

mobility in male partners of sub-fertile couples (Hauser et al., 2003).

third study failed to demonstrate any correlation (Bohannon et al., 2000).

(Gladen et al., 2003).

milk (PAN, 2012).

*7.2.2. Other endocrine conditions*

In mice, maternal doses of 26 mg/kg/day DDT from gestation through to lactation resulted in impaired learning in maze tests.

#### *7.1.2. Cancer*

The evidence relating to DDT and carcinogenicity provides uncertain conclusions. It has in‐ creased tumour production, mainly in the liver and lungs, in test animals such as rats, mice and hamsters in some studies, but not in others. In rats, liver tumours were induced in three studies at doses of 12.5 mg/kg/day over periods of 78 weeks to life, and thyroid tumours were induced at doses of 85 mg/kg/day over 78 weeks. Tests have shown laboratory mice were more sensitive to DDT. Life time doses of 0.4 mg/kg/day resulted in lung tumours in the second generation and leukaemia in the third generation, and liver tumours were in‐ duced at oral doses of 0.26 mg/kg/day in two separate studies over several generations (PAN, 2012).

#### **7.2. Humans**

The US Department of Health and Human Services (DHHS) has determined that "DDT may reasonably be anticipated to be a human carcinogen". DHHS has not classified DDE and DDD, but the US Environmental Protection Agency (EPA) has stated that they are probable human carcinogens (PAN, 2012), suspecting DDT, DDD and DDE of being environmental endocrine disrupters (Colburn et al., 1996) which may affect human health. Based on the re‐ sults of animal studies, DDT was suspected to cause cancer, diabetes, neurodevelopmental deficits, pregnancy and fertility loss (Beard, 2006). However, available epidemiological stud‐ ies reject DDT contribution in the development of these diseases and results are still unclear (Beard, 2006).

#### *7.2.1. Reproductive disorders*

*In vitro* studies have shown DDT and its metabolites to have human estrogenic activity (Chen et al., 1997) and DDE to act as an androgen antagonist (Kelce et al., 1995). Some re‐ searchers have also hypothesized a trend for decreasing semen quality in the general human community following the introduction of DDT (Carlsen et al., 1992; Sharpe & Skakkebaek, 1993) suggesting that environmental exposure to OCs may be causing human endocrine dis‐ ruption. However, the observed patterns may simply reflect geographic variations and life‐ style factors (Hauser et al., 2002).

Much of the epidemiologic research about the possible influence of pesticide exposure in general on pregnancy outcome suffers from significant methodological problems. The larg‐ est and most rigorous study of DDT and adverse reproductive outcomes was conducted in a US perinatal cohort of over 44,000 children born between 1959 and 1966 (Longnecker et al., 2001). DDE concentration was estimated in stored serum taken during pregnancy from mothers of 2380 children. Increasing concentrations of serum DDE were statistically and sig‐ nificantly related to preterm births, intra-uterine growth retardation (Siddiqui et al., 2003) and maternal diastolic blood pressure (Siddiqui et al., 2002). On the other hand, other stud‐ ies have failed to find any relationship between maternal DDT exposure and birth weight (Gladen et al., 2003).

Both animal models and early human studies have suggested a link with exposure to the DDT and the most common adverse pregnancy outcome (spontaneous abortion) (Saxena et al., 1980). However, the results of recent research are inconsistent. One small case-control study nested in a longitudinal study of Chinese textile workers found significantly higher levels of DDE in women with spontaneous abortion than full term controls. (Korrick et al., 2001) On the other hand, other studies have been unable to find an association (Gerhard et al., 1998). Unclear findings have been identified about the impact of DDT on fertility (Cohn et al., 2003): the probability of daughters' pregnancy fell with increasing levels of DDT in maternal serum, but it increased with increasing levels of DDE. Finally, OCs appear to trans‐ fer freely across the placenta from mother to foetus and could be also excreted in human milk (PAN, 2012).

In the late 1960s, concentrations of DDE in animals and first-trimester human fetal tissues correlated with reproductive abnormalities in male offspring such as hypospadias and un‐ descended testes (Gray et al., 2001). A case-control study nested in a US birth cohort (1959– 1966) (Longnecker et al., 2002) showed small increases in crypt-orchidism, hypospadias, and polythelia among boys with the highest DDE maternal serum levels when compared with those with the lowest maternal levels, although none of these were statistically significant. On the other hand, other studies failed to find a significant association between influence of DDT exposure on hormone levels in adult men, or DDT levels and sperm concentration/ mobility in male partners of sub-fertile couples (Hauser et al., 2003).

#### *7.2.2. Other endocrine conditions*

*7.1.1. Reproductive and teratogenic effects (birth defects)*

344 Insecticides - Development of Safer and More Effective Technologies

in impaired learning in maze tests.

*7.1.2. Cancer*

(PAN, 2012).

**7.2. Humans**

(Beard, 2006).

*7.2.1. Reproductive disorders*

style factors (Hauser et al., 2002).

DDT causes adverse reproductive and teratogenic effects in test animals. In one rat study, oral doses of 7.5 mg/kg/day for 36 weeks resulted in sterility. In rabbits, doses of 1 mg/kg/day administered on gestation days 4-7 resulted in decreased foetal weights. In mice, doses of 1.67 mg/kg/day resulted in decreased embryo implantation and irregularities in the oestrus cycle over 28 weeks (Agency for Toxic Substances and Disease Registry, 1994). Many of these observations may be the result of disruptions to the endocrine (hormonal) system.

In mice, maternal doses of 26 mg/kg/day DDT from gestation through to lactation resulted

The evidence relating to DDT and carcinogenicity provides uncertain conclusions. It has in‐ creased tumour production, mainly in the liver and lungs, in test animals such as rats, mice and hamsters in some studies, but not in others. In rats, liver tumours were induced in three studies at doses of 12.5 mg/kg/day over periods of 78 weeks to life, and thyroid tumours were induced at doses of 85 mg/kg/day over 78 weeks. Tests have shown laboratory mice were more sensitive to DDT. Life time doses of 0.4 mg/kg/day resulted in lung tumours in the second generation and leukaemia in the third generation, and liver tumours were in‐ duced at oral doses of 0.26 mg/kg/day in two separate studies over several generations

The US Department of Health and Human Services (DHHS) has determined that "DDT may reasonably be anticipated to be a human carcinogen". DHHS has not classified DDE and DDD, but the US Environmental Protection Agency (EPA) has stated that they are probable human carcinogens (PAN, 2012), suspecting DDT, DDD and DDE of being environmental endocrine disrupters (Colburn et al., 1996) which may affect human health. Based on the re‐ sults of animal studies, DDT was suspected to cause cancer, diabetes, neurodevelopmental deficits, pregnancy and fertility loss (Beard, 2006). However, available epidemiological stud‐ ies reject DDT contribution in the development of these diseases and results are still unclear

*In vitro* studies have shown DDT and its metabolites to have human estrogenic activity (Chen et al., 1997) and DDE to act as an androgen antagonist (Kelce et al., 1995). Some re‐ searchers have also hypothesized a trend for decreasing semen quality in the general human community following the introduction of DDT (Carlsen et al., 1992; Sharpe & Skakkebaek, 1993) suggesting that environmental exposure to OCs may be causing human endocrine dis‐ ruption. However, the observed patterns may simply reflect geographic variations and life‐ Bone mineral density, which is regulated by the antagonistic effect of androgens and oestro‐ gens, may be another possible target of endocrine disruption. DDT has been shown to mod‐ ulate trophoblast calcium handling functions *in vitro* (Derfoul et al., 2003) and two small cross-sectional studies have suggested there may be a weak association between serum DDE levels and reduced bone mineral density (Beard et al., 2000; Glynn et al., 2000). However, a third study failed to demonstrate any correlation (Bohannon et al., 2000).

*In vitro* studies suggest that DDT and its metabolites do not influence thyroid metabolism (Langer et al., 2003; Rathore et al., 2002). Other research has failed to find a significant associa‐ tion with endometriosis, a hormone dependant pelvic inflammatory disease (Lebel et al., 1998).

### *7.2.3. Cancer*

Breast cancer has been studied most rigorously; even though the majority of results showed no causative association with DDT exposure (Beard et al., 2006), the latest evidence indicates an increased risk in women who were exposed at a young age. It was hypothesised that DDT co-genres and metabolites might act as tumour promoters in hormonally sensitive can‐ cers due to their oestrogenic and anti-androgenic properties (Iscan et al., 2002). More recent‐ ly, larger and better designed studies have generally not supported this hypothesis (Calle et al., 2002; Snedeker, 2001). Other hormonally sensitive cancers include cancer of the endome‐ trium and prostate. Two case-control studies have explored the possibility that DDT may be related to endometrial cancer with neither finding a significant association (Sturgeon et al., 1998; Weiderpass et al., 2000). On the other hand, an Italian hospital-based multisite casecontrol study of prostate cancer found an increased risk among farmers exposed to DDT (Settimi et al., 2003), although exposure assessment in this study relied on self-report, leav‐ ing these findings susceptible to recall bias. Rates of prostate cancer were also found to be increased among male applicators using chlorinated pesticides in the Agricultural Health Study cohort (Alavanja et al., 2003) and in a Swedish cohort of pesticide applicators (Dich & Wiklund, 1998).

posed to pesticides including DDT also scored worse than non-exposed subjects on a selfreported neuropsychological questionnaire of surviving members of a historical cohort of

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347

At least one cross-sectional study has associated DDT and other pesticide exposures with

Diabetes has been associated with OC exposure in at least one study. An Australian cohort study of mortality in staff working as part of an insecticide application program also found increased mortality from pancreatic cancer in DDT-exposed subjects and from diabetes in

It is only in the last 25 years that more rigorous epidemiological research has focused on the possible adverse effects of exposure to DDT in humans. Unfortunately, they are not easily answered since epidemiologic research in this field is plagued by methodological challenges (Blondell, 1990). Fewer early human studies have been undertaken specifically on DDT, moreover they were small and limited in scope. A major methodological challenge is the dif‐ ficulty in getting accurate information on subject exposure since many of the possible ad‐ verse effects of DDT (for example, cancer) may not become evident until many years after a causative exposure. Moreover, since it is rare for past exposure to have been accurately re‐ corded at the time, exposure estimation has often been based on the response by subjects to questioning. However, subjects may have been unaware of significant past exposures to DDT through the food chain and even occupationally exposed subjects are unlikely to accu‐ rately remember and quantify exposures faced 20–30 years in the past. In the absence of a recorded exposure history, biological sampling of subjects may give some measure of their past exposure. Unlike other pesticides, DDT and DDE are only very slowly eliminated, mak‐ ing biological monitoring a relatively accurate, easy and cheap means of assessing past ex‐ posure. Serum levels of DDT and DDE are closely correlated with levels in adipose tissue and thus provide a relatively non-invasive measure (Mussalo-Rauhamaa, 1991). Unfortu‐ nately, biological monitoring of DDT presents its own potential for epidemiological bias since levels can also be influenced by factors that relate directly to the outcome of interest, in

Since DDT and its metabolites are so persistent in the environment and human tissues, hu‐ mans are not excluded from this ecological trends raising questions about the possible im‐ pact of widespread pesticide exposure on human communities. Biological sampling near the time of peak use during the 1960s showed increasing DDT levels in most human communi‐ ties, mainly due to exposure to residues in food. High levels of human exposure to DDT among those living in sprayed houses, most of whom are living under conditions of poverty

suppression or induction of several immune parameters (Daniel et al., 2002).

pesticide applicators (Beard, 2006).

**7.3. Epidemiological studies**

particular weight change.

subjects working with any pesticide (Beard, 2006).

*7.2.5. Immune system*

*7.2.6. Diabetes*

Pesticides have been associated with pancreatic cancer (Beard, 2006). A large Norwegian prospective study of lifestyle factors and pancreatic cancer identified a higher risk among men occupied in farming, agriculture or forestry (Nilsen & Vatten, 2000). Recent research lends a physiological plausibility to a possible association between DDT and pancreatic cancer by suggesting that DDT may modulate oncogene expression or provide a growth advantage to mutated cells, for example, through its actions as an endocrine disrupter (Porta et al., 1999).

Case control studies using self-reported exposure have found significant associations be‐ tween DDT exposure and lung cancer, leukaemia and non-Hodgkins lymphoma (NHL) (Beard, 2006). However a nested case-control study using stored serum identified a dose re‐ sponse relationship for NHL with PCB exposure but not DDT. A small case-control study using serum levels drawn at diagnosis has suggested an association between DDT exposure and colorectal cancer.

#### *7.2.4. Nervous system*

Animal studies have suggested DDT may cause central nervous system (CNS) toxicity (Eriksson & Talts, 2000). Exposure to DDT may be associated with a permanent decline in neurobehavioral functioning and an increase in psychiatric symptoms, but the few studies and limited exposure information made it impossible to be confidant about this potential re‐ lationship (Colosio et al., 2003). These findings are also complicated by potential confound‐ ing from exposure to other pesticides, such as organophosphates, that are known to have neurological effects. One recent case study suggested that DDT may be related to neurologi‐ cal impairment (Hardell et al., 2002). Another recent study of retired malaria-control work‐ ers found various neurobehavioral functions and performance deteriorated significantly with increasing years of DDT application (van Wendel de Joode et al., 2001). Subjects ex‐ posed to pesticides including DDT also scored worse than non-exposed subjects on a selfreported neuropsychological questionnaire of surviving members of a historical cohort of pesticide applicators (Beard, 2006).

#### *7.2.5. Immune system*

At least one cross-sectional study has associated DDT and other pesticide exposures with suppression or induction of several immune parameters (Daniel et al., 2002).

#### *7.2.6. Diabetes*

*7.2.3. Cancer*

346 Insecticides - Development of Safer and More Effective Technologies

Wiklund, 1998).

(Porta et al., 1999).

and colorectal cancer.

*7.2.4. Nervous system*

Breast cancer has been studied most rigorously; even though the majority of results showed no causative association with DDT exposure (Beard et al., 2006), the latest evidence indicates an increased risk in women who were exposed at a young age. It was hypothesised that DDT co-genres and metabolites might act as tumour promoters in hormonally sensitive can‐ cers due to their oestrogenic and anti-androgenic properties (Iscan et al., 2002). More recent‐ ly, larger and better designed studies have generally not supported this hypothesis (Calle et al., 2002; Snedeker, 2001). Other hormonally sensitive cancers include cancer of the endome‐ trium and prostate. Two case-control studies have explored the possibility that DDT may be related to endometrial cancer with neither finding a significant association (Sturgeon et al., 1998; Weiderpass et al., 2000). On the other hand, an Italian hospital-based multisite casecontrol study of prostate cancer found an increased risk among farmers exposed to DDT (Settimi et al., 2003), although exposure assessment in this study relied on self-report, leav‐ ing these findings susceptible to recall bias. Rates of prostate cancer were also found to be increased among male applicators using chlorinated pesticides in the Agricultural Health Study cohort (Alavanja et al., 2003) and in a Swedish cohort of pesticide applicators (Dich &

Pesticides have been associated with pancreatic cancer (Beard, 2006). A large Norwegian prospective study of lifestyle factors and pancreatic cancer identified a higher risk among men occupied in farming, agriculture or forestry (Nilsen & Vatten, 2000). Recent research lends a physiological plausibility to a possible association between DDT and pancreatic cancer by suggesting that DDT may modulate oncogene expression or provide a growth advantage to mutated cells, for example, through its actions as an endocrine disrupter

Case control studies using self-reported exposure have found significant associations be‐ tween DDT exposure and lung cancer, leukaemia and non-Hodgkins lymphoma (NHL) (Beard, 2006). However a nested case-control study using stored serum identified a dose re‐ sponse relationship for NHL with PCB exposure but not DDT. A small case-control study using serum levels drawn at diagnosis has suggested an association between DDT exposure

Animal studies have suggested DDT may cause central nervous system (CNS) toxicity (Eriksson & Talts, 2000). Exposure to DDT may be associated with a permanent decline in neurobehavioral functioning and an increase in psychiatric symptoms, but the few studies and limited exposure information made it impossible to be confidant about this potential re‐ lationship (Colosio et al., 2003). These findings are also complicated by potential confound‐ ing from exposure to other pesticides, such as organophosphates, that are known to have neurological effects. One recent case study suggested that DDT may be related to neurologi‐ cal impairment (Hardell et al., 2002). Another recent study of retired malaria-control work‐ ers found various neurobehavioral functions and performance deteriorated significantly with increasing years of DDT application (van Wendel de Joode et al., 2001). Subjects ex‐ Diabetes has been associated with OC exposure in at least one study. An Australian cohort study of mortality in staff working as part of an insecticide application program also found increased mortality from pancreatic cancer in DDT-exposed subjects and from diabetes in subjects working with any pesticide (Beard, 2006).

#### **7.3. Epidemiological studies**

It is only in the last 25 years that more rigorous epidemiological research has focused on the possible adverse effects of exposure to DDT in humans. Unfortunately, they are not easily answered since epidemiologic research in this field is plagued by methodological challenges (Blondell, 1990). Fewer early human studies have been undertaken specifically on DDT, moreover they were small and limited in scope. A major methodological challenge is the dif‐ ficulty in getting accurate information on subject exposure since many of the possible ad‐ verse effects of DDT (for example, cancer) may not become evident until many years after a causative exposure. Moreover, since it is rare for past exposure to have been accurately re‐ corded at the time, exposure estimation has often been based on the response by subjects to questioning. However, subjects may have been unaware of significant past exposures to DDT through the food chain and even occupationally exposed subjects are unlikely to accu‐ rately remember and quantify exposures faced 20–30 years in the past. In the absence of a recorded exposure history, biological sampling of subjects may give some measure of their past exposure. Unlike other pesticides, DDT and DDE are only very slowly eliminated, mak‐ ing biological monitoring a relatively accurate, easy and cheap means of assessing past ex‐ posure. Serum levels of DDT and DDE are closely correlated with levels in adipose tissue and thus provide a relatively non-invasive measure (Mussalo-Rauhamaa, 1991). Unfortu‐ nately, biological monitoring of DDT presents its own potential for epidemiological bias since levels can also be influenced by factors that relate directly to the outcome of interest, in particular weight change.

Since DDT and its metabolites are so persistent in the environment and human tissues, hu‐ mans are not excluded from this ecological trends raising questions about the possible im‐ pact of widespread pesticide exposure on human communities. Biological sampling near the time of peak use during the 1960s showed increasing DDT levels in most human communi‐ ties, mainly due to exposure to residues in food. High levels of human exposure to DDT among those living in sprayed houses, most of whom are living under conditions of poverty and often with high levels of immune impairment, have been found in studies in South Afri‐ ca and Mexico (Aneck-Hahn et al., 2007; Bouwman et al., 1991; De Jager et al., 2006; Yanez et al., 2002), but contemporary peer-reviewed data from India, the largest consumer of DDT, are lacking. The simultaneous presence of, and possible interaction between, DDT, DDE and PYs in human tissue is another area of concern (Bouwman et al., 2006; Longnecker, 2005). In North America, rather high levels of exposure have been recorded in biological samples col‐ lected in the 1960s (Eskenazi et al., 2009). DDT accumulates in fatty tissue and is slowly re‐ leased. The half-life of DDT in humans is > 4 years; the half-life for DDE is probably longer (Longnecker, 2005).

**Alternatives to DDT**

indoor residual

insecticide-

irrigation

microbial

polystyrene

**8.1. Chemical methods**

to come to market in the short term.

**Chemical (yes/no)**

**Vector**

**stage Availability Delivery/Resources Risk**

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private sector resistance, toxicity

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349

spraying yes adult available spray teams resistance, toxicity

management no larva available local, irrigation sector negligible

larvicides no larva available programs, private sectors resistance

beads no larva available local negligible predation no larva available local, programs, agriculture sector negligible repellents yes adult under development local, private sector resistance, toxicity

The strength of IRS with insecticides lies in its effect on shortening the life span of adult mosquitoes near their human targets (MacDonald, 1957). Two new approaches are currently being developed with regard to IRS, including some existing insecticides not currently avail‐ able for public health (chlorfenapyr and indoxacarb), potentially effective in areas with pyr‐ ethroid resistance (N'Guessan et al., 2007a; N'Guessan et al., 2007b), and new formulations

The main alternative to IRS are ITNs, which have been shown convincingly to substantially reduce all-cause child mortality, under both experimental (Lengeler, 2004) and operational conditions (Schellenberg et al., 2001; Fegan et al., 2007). Various new developments in ITN technology have spread recently. At least one nonpyrethroid insecticide with novel chemis‐ try has been developed for ITNs (Hemingway et al., 2006) to cope with the problem of re‐ sistance; however, safety issues are still a concern. Other new ITN products are not expected

Chemical insecticides as larvicides can play an important role to control mosquito breeding

Moreover, in order to push away mosquitoes, which usually are attracted by the moisture, warmth, carbon dioxide or estrogens from human skin, a large spectrum of repellents have been developed and are currently used; these substances, manufactured in several forms, in‐ cluding aerosols, creams, lotions, suntan oils, grease sticks and cloth-impregnating laundry emulsions, are usually applied on the skin or clothes, and produce a vapor layer character‐ ized by bad smell or taste to insects (Brown & Hebert, 1997). The ideal repellent should sat‐ isfy several criteria: a) have long-lasting effectiveness; b) do not irritate human skin; c) have

of existing insecticides with prolonged residual activity (Hemingway et al., 2006).

in urban settings, but they are a concern to the integrity of aquatic ecosystems.

treated bednets yes adult available free distribution, social marketing,

**Table 1.** Alternative methods for malaria vector control. Adapted from (van den Berg, 2009)
