by Dr. Fina P.Kaloyanova-Simeonova

The organochlorine pesticides cover a wide range of chemical structures: compounds of cyclodiene series such as aldrin, dieldrin, endrin, heptaclor, chlordane, toxaphene; halogenated ethane derivatives such as DDT; cycloparaffins such as hexachlorcyclohexane; benzene hexachoride /HCB/ and chlorinated terpens. Several of the organochlorine pesticides are the most persistent types of pesticides and these compounds create most concern for problems of translocation and biomagnification. The number of published papers on human, environmental and laboratory studies is considerable. This review covers available publications after 1995.

CONCENTRATIONS OF ORGANOCHLORINE PESTICIDES IN HUMAN TISSUES

The presence of persistent organochlorine pesticides /OCI/ in human serum and adipose tissues has been reported in many studies over the last four decades. Data are summarized and evaluated in the respective EHC documents, Murphy /1986/, Kaloyanova and El Batawi /1991/.

The most recent data on the concentrations of OCI in human tissues are presented in table 1.

Sheele /1998/ compared the concentrations of OCI in fat tissues and bone marrow. The level of p,p’DDT was three fold lower in bone marrow and the level of HCH was eight fold lower. The concentration of p,p’DDE in bone marrow was 77% of the concentration in fat tissues. Whereas the concentration of b HCH was 41% of adipose tissues a HCH and dieldrin were increase 10-19 -fold respectively.

Close relationship was found between total DDT in adipose tissues and milk fat /Dorea et all 1977/. No significant relationship was found between serum concentrations and breast fat tissues /Archibeque- Engle 1997/.

CONCENTRATIONS OF OCI IN HUMAN MILK

There are limited study on the OCI concentrations in human milk./ Table 2/. In Egypt the levels found are lower than the levels reported a number of years ago in most of the developed countries. Higher levels are recorded in the samples from intensive agricultural activity regions./ Saleh et all 1995/ Aldrin and endrin were not detected in most of the samples.

Estimated daily intake of DDT complex and lindane by breast fed infants were 86% and 3% of the respective ADIs. / Dogheim et all 1996/

Occurrence of persistent OCI in human milk is reported in Czech Republic such as DDT and metabolites, HCH, and HCB. / Schoula et all 1996/.

Chikuni et all /1997/ detected OCI in 98-100 % of the samples. The ratio of DDT/DDE was high in some area in Zimbabwe, suggesting recent pollution by DDT used for vector control.

For high levels of b HCH in human milk in Kazakstan reported Hopper et all /1997/.

Al Saleh et all /1998/ found in Saudi Arabia different DDT metabolites in 75% of samples, lindan in 24 %, heptachlor in 21 %, heptachlor epoxide in 34%, dieldrin in 49%, and endrin in 32%. The maximum daily intakes exceeded ADI for 5 kg infant. Dieldrin and heptachlor epoxide were detected in 43 and 30% of samples respectively in Australia /Victoria/. A number of infants had daily intakes above the ADI for total chlordane, total DDT, dieldrin, and heptachlor epoxide./ Quinsey et all 1995/.

The levels of OCI in human milk increased with the maternal age./Brunetto et all 1996, Czaja et all 1997/. They may be related to the dietary regimen to breast fed mothers /Cavaliere et all 1997/. Both conclusions are supported in the study of Schlaud et all /1995/ . They recommended breast feeding women to reduce OCI residues levels in the short term, by keeping their weight until after lactation. Lower dietary fat intake may reduce the lifetime accumulation of OCI.

In USA DDT metabolites have been detected at elevated concentrations in sediment and fish in Yakima river Washington. / Marien and Laflamme 1995/ The authors concluded that mothers who frequently consume bottom-feeding fish could have breast milk with DDT concentrations sufficiently high to expose their infants to levels above the tolerable daily intake.

PERSISTENT OCI IN FOOD PRODUCTS

Public concern about the adverse environmental and human health impact of OCI led to strict regulations of their use in developed countries more than two decades ago. Nevertheless DDT and lindane and several other OCI are still being used for agriculture and public health program in developing countries. As a consequence humans in these regions are exposed to greater dietary levels of OCI. Due to the globalization of the trade of food almost all countries in the world may be subject of their impact.

Some data for OCI concentrations in food are given on table 3.

In Poland DDT was found in 100% milk samples, lindane in 60%, a HCH in 30%, and

others only in some samples. Levels of DDT in animal fat decreased 20-fold for the period 1970 to 1990/94, and 10-fold in bovine milk. /Niewiadowska et all 1995, Niewiadowska and Zmudzki 1996/

Dietary intake of fish from Baltic Sea contaminated with persistent OCI is related with the risk of having an infant with low weight. /Rylander et all 1996/

The levels of DDT and HCH in total diet in Netherlands did not exceed the ADI or comparable values in any of age-sex groups /Brussaard et all 1996/.

Dietary intake in Spain were all below the respective ADI or Provisional Tolerable Weakly Intake. Only lindane was much higher /Urieta et all 1996/.

Losada et all /1996/ confirm this results ranging lindane and aldrin as a pesticides with the highest incidence percentage of the 10 persistent OCI measured in milk from Spain-Leon. None of samples analyzed exceeded the maximum level allowed by the EU. The data of Martinez et all/1997/ for Spain are to some extent different. The authors found

95% positive samples for HCH isomers and 13% of them exceeded the MRL of EU. Chlordane was found in 75% of samples at higher concentrations, and some samples heptchlor epoxide. Only DDT group didn’t exceed the limit.

Kannan et all /1997/ reviewed the published information on OCI in foodstuffs from South and Southeast Asia, and Oceanic countries. In India concentrations of DDT and HCH have declined more than two orders of magnitude in farms products /food grains and vegetables/ in two decades. Milk and milk products are the major route of exposure. Data are close to or above to MRLs of FAO/WHO. Dietary intakes of DDT and HCH by Indians are 100 fold that of more developed nations. Aldrin, dieldrin, and heptachlor have been measured in vegetables and sporadic incidences of greater concentrations ./>1 m /g found/. In most southeast Asian countries DDT was common contaminant in animal origin foodstuffs, due to the recent use of DDT in vector control operations. Dietary intake were about 10 times more than the more developed countries. DDT, aldrin and dieldrin were detected in meat in Thailand and Malaysia. In South Pacific countries /Australia, New Zealand / chlordane’s were the most prevalent OCI in foodstuffs. Meat and fish were the major source of OCI in Australia. Current intake of OCI of developing countries in Asia is at least 5-100 fold greater than those in more developed countries, suggesting a greater risk. Malnutrition contributes to the risk. The estimated intake of DDT by infants was at least 100 fold greater than ADI. In addition to DDT, exposure to HCH and dieldrin may cause adverse effects to infants because they are more vulnerable to toxic effects.

In China 69% of samples are positive for HCH, 42% for DDT. All are less than National Standards of food Hygiene /Zhang et all 1997/ Compared to 1970s OCI residues in China have decreased significantly.

In Japan daily intake of total HCH, dieldrin and total DDT in1992/3 decreased 29 and 40% respectively, but lindane intake increased 167% in comparison with 1980/84. It was shown that this is due to recent increase of the imported meat and meat products. In Egypt aldrin, dieldrin, endrin, and heptachlor were not detected in food of animal origin. /Dogheim et all 1996/. Levels of HCH and DDT, and heptachlor exceeded the Marls in small number of fish samples. No OCI were found in citrus fruits. Residues of HCH and HCH in some samples of potatoes are related to illegal use of these

pesticides banned in Egypt since 1980 /Dogheim et all 1996/.The percentage of positive samples of butter in Mexico is for lindane 91, HCH -90, DDE-88, heptachlor epoxide-7 /Waliszewski et all 1996c/. In Nicaragua DDT was detected in 81% of samples and other OCI only in single samples. DDT was used for cotton production. / Zapata Moran 1996/.

MECHANISM OF ACTION

Estrogen stimulation

Some persistent OCI /DDT, toxaphene, methoxichlor/ can interfere with estrogen and androgen receptors. Thus they can potentially interact with many physiologic processes through numerous receptor signaling pathways. /von Saal et all 1995, Fry 1995, Guillette et all 1996, Sheklar et all 1997, Klotz et all 1977, Crain et all 1998/.p,p’DDT is more potent estrogen than o,p’DDT but it is less effective than o,p’DDT in inhibiting of estradiol to estrogen receptor. Heptachlor is estrogenic as well./Shekhar et all 1997/. In estrogen receptor positive breast cancer cells, p,p’DDT evokes responses by itself and enhances the responses in collaboration with estradiol or o,p’DDT..

The estrogen action of some persistent OCI may play role in the progression of hormonally responsive tumors of the breast and uterus. Steimetz et all /1996/ found that b HCH and o,p’DDT stimulated proliferation in dose dependent manner in the estrogen receptor positive human breast cells. HCH produce estrogen like effects through non classic mechanism and therefore may be of concern with regard to breast and uterus cancer risk. Similar are the results of Shen and Novak /1997/. Enan and Matsumura /1998/ in vitro experiments demonstrated a different mechanism of OCI on tumor cell not related to estrogen receptors. Dees et all /1997/concluded that the role for OCI in breast cancer etiology remains controversial. Effects on behaviour of o,p’DDT and methoxyclor were mediated by binding to estrogen receptors in the developing brain./vom Saal et all 1995/

Immune system

OCI may modulate the immune response. Banerjee et all/1997/ evaluated the humoral immune response of DDT to mice. Combined with stress DDT /50-100 ppm in diet for 4 weeks/ suppressed the primary response to cheep red blood cells and the anti-titers were lower the control values. Possible interaction between physical, emotional and environmental xenobiotic stressors in the regulation of humoral immune response are possible.

Immunomodulatory effect of DDT was demonstrated in rats as well. Humoral and cell mediated immune responses to ovalbumin were studied /Banerjee et all 1996/. Different degrees of suppression was demonstrated at 200 ppm DDT in food for 6 weeks such as suppression of IgM and IgG levels, reduced antibody response, inhibition of leucocyte and macrophage migration factors, delayed type of hypersensitivity. The authors discuss the importance of these facts as a determinant of the toxicity of DDT and its influence in health and diseases. Similar is the conclusion of Lahvis et all/1995/ for the role of immune system dysfunction due to OCI in dolphins.

A high content of lindane /0.139 mg/kg/ in stable dust is supposed to participate in the immunosuppression of limphocyte in cattles /Raszyk et al 1997/

Mixed function oxidase system

Mixed function oxidase system in hepatic and extrahepatic tissues was studied using different methodes /Haltokar and Pawar 1995, Ferreira et all 1997, Kostka et all 1997/. It was demonstrated that DDT induced the phenobarbital-type of cytochrome P450 2B form in rat liver. At high concentration it is uncoupling oxidative phosphorylation, related to deleterious effects on the integrity of the mitochondrial membrane. Hepatocyte proliferation preceeding hepatomegaly, accompanied by an increase in the p-nitroanisole O-demethylase activity was reported / Kostka et all 1996/.

Sodium channels

Ion channels are primary sites for several groups of insecticides. The voltage sensitive sodium channel is the major target site for DDT and pyrethroids. /Bloomquist 1996/.

Endosulfan which is potent convulsant block chloride channel. Stress is given to the combine effect of pesticides with similar mechanism of action. Bioalethrin causes permanent changes in behavioural and muscarin acethylcholine receptor variables in adult mice exposed neonatally to DDT./Johansson et all 1995/.

EPIDEMIOLOGICAL STUDIES ON CARCENOGENICITY OF OCI

Breast cancer

Possible links between exposure to DDE, the persistent metabolite of DDT and breast cancer in case-control studies in European countries: Germany, Netherlands, Northern Ireland, Switzerland and Spain was studied / van’t Veer et all 1977/. Women with breast cancer had adipose tissues concentrations 9.2% lower than control women. No increased risk of breast cancer was found at higher concentrations. This study does not support the hypothesis that DDT increases risk of breast cancer in postmenopausal women in Europe. Hunter et all /1997/ compared the DDT blood levels and the risk of breast cancer. Their data /4.7 ppb - 5.35 ppb control/ do not support the hypothesis that exposure to DDT increases the risk of breast cancer. Schecter et all /1997 b/ performed similar study among women living in the north of Vietnam. The results suggest that recent and past exposure to DDT does not play important role in the etiology of breast cancer among women living in a countries with tropical climate where insecticide use for mosquito control is common.

Lopes-Carrillo et all/ 1996 and 1997/ reached the same conclusion for women with serum levels of DDE /in lipid/ 562 ppb but they do not exclude the possibility that higher levels of exposure could still play a role in ethiology of breast cancer.

Occupational exposure to relatively high levels of DDT is not associated with an increased incidence of breast cancer /Safe 1997, Safe and Zahcharevski 1997/

The hypothesis that human exposure to OCI would favor on estrogenic overactivity leading to an increase in estrogen-dependent formation of mammary or endometrial tumors is not supported by the existing in vitro, animal and epidemic evidence. It can however not be conclusively rejected on the basis of available data/ Ahlborgh et all 1995/

Other factor may contribute as well . Higher risk may occur among persons whose enzymes either are more active in the production of procarcinogens or fail to detoxify carcinogenic intermediates formed from chemicals in the environment /Wolf and Weston 1997/. Interaction between non genotoxic carcinogens may increase the carcenogenic risk /Bessi et all 1995/. Verma et all 1997 recommended soybeans in diet in order to prevent eventually hormone related cancers.

Further studies are recommended as it is well known that the breast cancer is strongly associated with reproductive hormones./ Wolff 1995/

Cancer on other organs or systems

In occupationally .exposed workers to DDT in Italy significant increase in risk for liver and biliary tract cancer was reported as well as multiple myeloma. and myeloid leukemia. Not trends occurred according to length of employment. These data are still preliminary according to the authors./ Cocco et all 1997/ There was not dose response relation between serum OCI in general population in nested case control study of non-Hodgkin limphoma / Rothman et all 1997/.

Workers exposed to DDT were subject to increased risk of lung cancer in Uruguay /De Stefani et all 1996/. DDT exposure is associated with increased risk of pancreas cancer in USA, Michigan /Fryzek et all/. Review on epidemiological data concluded that no convincing evidence exist that OCI cause a large excess number of cancers.

/Longnecker et all 1997/.

Other effects

Unexplained and persistent fatigue was related with DDT and HCH exposure.

/Dunstan et all 1996/. Neurotoxicity risk is very important and should be considered in development neurotoxicity ./Evangelista de Duffard and Duffard 1996/

The sinergic or additive effects of DDT in combination with other toxic pollutants in Great Laces USA may be causing adverse effects on reproduction in sensitive individuals, which need to be explored /Foster 1995/.

CONCLUSION

The early findings in 1950s, 1960, and 1970, of persistent OCI in birds and fish population as a result of biomagnification in North America and Europe followed by publication in Baltic Sea, Danube basin and India were obviously the result of deliberate and extensive use of these chemicals in agriculture and public health. The threat to groundwater resources from infiltration of OCI in soils, alarming reports on contamination of mothers milk and storage in human tissues have been described in many parts of the world /Bro Rasmussen/1996/.

We have to day knowledge on fundamental process such as environmental transport and transformation, exposure , uptake and metabolic patterns. We are informed of the most obvious cause effects chains. In spite of this experience the problem of contamination is still existing ever increasing due to the frequency of reported accidents and damages from all over the world and the controversy and uncertainty in some statements. The use of persistent OCI have been banned or severely restricted to use only in small number of countries with serious public health problems such as malaria and other parasitic diseases. It is obvious therefore that the question is still matter of concern for the global society and a call for world wide attention through international bodies.

The problem, is complicated by the reemerging of malaria in many countries particularly in South America, and Asia /Roberts et all 1997, Kannan et all 1977/. There is casual link between decreased spraying of homes with DDT and increased malaria. Equador, which has increased use of DDT since 1993 is the only South America country reporting large reduction /61%/ in malaria rate since 1993. Cost versus benefits of DDT and alternative insecticides is a subject of urgent to be discussed by international organizations.

Scientific interest concerning the effects of persistent OCI continues. Considerable number of research projects have been performed and results published in the period after 1995. They cover all aspect of OCI -environmental pollution, storage in humans and aquatic and terrestrial life and adverse effects, mostly carcenogenicity.

Epidemiological studies in this field are of great importance and should have priority.