Try out PMC Labs and tell us what you think. Learn More. Dichlorodiphenyltrichloroethane DDT is still used in certain areas of tropics and subtropics to control malaria and other insect-transmitted diseases. DDT and its metabolites have been extensively studied for their toxicity and carcinogenicity in animals and humans and shown to have an endocrine disrupting potential affecting reproductive system although the effects may vary among animal species in correlation with exposure levels.
Epidemiologic studies revealed either positive or negative associations between exposure to DDT and tumor development, but there has been no clear evidence that DDT causes cancer in humans. In experimental animals, tumor induction by DDT has been shown in the liver, lung, and adrenals. The mechanisms of hepatic tumor development by DDT have been studied in rats and mice.
DDT is known as a non-genotoxic hepatocarcinogen and has been shown to induce microsomal enzymes through activation of constitutive androstane receptor CAR and to inhibit gap junctional intercellular communication GJIC in the rodent liver.
Oxidative stress could be a key factor in hepatocarcinogenesis by DDT. DDT dichlorodiphenyltrichloroethane was first synthesized in and its insecticidal properties were discovered in Since then DDT was widely used in the world to control insects on agricultural crops and those that carry diseases such as malaria and typhus. However, the use of this compound has been banned in many countries since s because of its chemical characteristics such as accumulation and bio-concentration in lipid systems of all animal species which may result in occurrence of potential adverse effects on humans and wild animals 1.
DDT has been suggested to be toxic to a range of wildlife including birds and marine animals, and its metabolite DDE dichlorodiphenyldichloroethylene causes eggshell thinning of certain bird species such as bald eagle and brown pelican, leading to declines of their populations 1 , 2.
It is considered that DDE inhibits calcium adenosine triphosphatase ATPase in the membrane of the shell gland and reduces the transport of calcium carbonate from blood into the eggshell gland 1.
Despite these circumstances, DDT is still used in the certain areas of tropics and subtropics for the control of malaria and other insect-transmitted diseases causing high death rates 3. DDT and its metabolites have been extensively studied for their toxicity and carcinogenicity in experimental animals and humans and the results of their investigations are well documented 1 , 4.
The present review paper describes the overview of neurotoxicity, reproductive toxicity with endocrine effects, hepatotoxicity and carcinogenicity of DDT and its metabolites. It is known that DDT delays the closing of the sodium ion channel and prevents the opening of the potassium gates and also targets a specific neuronal ATPase considered to be involved in the control of the rate of sodium, potassium, and calcium fluxes through the nerve membrane 1.
In addition, DDT has been suggested to inhibit the ability to transport calcium ions which are essential to the release of neurotransmitters. These actions combine to effectively maintain the depolarization of the nerve membrane, potentiating the release of transmitters and leading to central nervous system excitation manifested as hyperexcitability, tremors, and convulusions. It was reported that occupational exposure to DDT in retired workers from Costa Rica was associated with neurobehabioral symptoms in a dose-response pattern This sex difference was consistent with the toxicokinetics data obtained from the rat 2-year study in that plasma and brain concentrations of DDT and its metabolite DDE tended to be higher in females than males Figs.
M male; F female. It has been suggested that DDT and its metabolites may have an endocrine disrupting potential to affect reproductive system through their estrogenic or androgenic activity 1. However, reproductive and postnatal developmental toxicities were not evident up to ppm high-dose except for the decreased pup viability index on postnatal day 21 in the high-dose group.
Hepatotoxicity and carcinogenicity of DDT have been demonstrated in animals to show increased liver weights, hepatocellular hypertrophy, microsomal enzyme induction similar to phenobarbital, and hepatocellular tumor induction 1.
Many epidemiologic studies have been conducted and the results indicate either positive or negative associations between exposure to DDT and tumor development in humans 1 , However, there has been no clear evidence that exposure to DDT causes cancer in humans.
The results are generally consistent with previous works 14 — 17 , 23 — 25 and considered due to activation of constitutive androstane receptor CAR This suggests that microsomal enzyme activity is not always consistent with its associated protein content and there seems to be an almost inverse correlation between the increase in PROD at different time points and the concurrent incidence of pre-neoplastic hepatocellular eosinophilic foci and hepatocellular tumors.
Since CYP3A2 is androgen-dependent and not normally expressed in adult female rats 25 , the induction of CYP3A2 by DDT in female rats suggests that DDT is able to modulate sexual metabolic dimorphism by affecting regulatory sites of hepatic metabolism With respect to other P isozyme contents, statistically significant increases or decreases in CYP1A2 and CYP4A1 were noted in the DDT-treated groups of both sexes, but those changes were not consistent during the study and their toxicological significance remains obscure.
These results indicate that hepatocytes in the DDT-treated livers are exposed to oxidative stress and could have cellular and DNA damages. It is postulated that the metabolic activation with enzyme induction of P by DDT may result in formation of reactive oxygen radicals 23 , In addition, it is conceivable that DDT or its metabolites may affect mitochondria and cause mitochondrial dysfunction which results in formation of deleterious reactive oxygen species ROS leading to lipid peroxidation since mitochondria are prominent target sites of many hepatotoxic chemicals and also the main source of ROS in the hepatocytes 6 — 9.
In our 2-year rat study, the appearance of eosinophilic altered hepatocellular foci AHF in the high-dose group was significantly earlier than that in controls. This result indicates that the occurrence of initiated cells could be accelerated by DDT in the high-dose group, which is considered to be due to hepatocellular DNA damage caused by oxidative stress.
It is possible that the accelerated occurrence of initiated cells may result in the early appearance and increased incidence of eosinophilic AHF described later. This cell proliferation pattern is consistent with that by non-genotoxic mitogenic hepatocarcinogens 28 — It is generally known that the hepatic cell proliferation response to non-genotoxic mitogenic hepatocarcinogens such as phenobarbital typically occurs through an initial burst of enhanced DNA synthesis followed by enhanced mitosis 29 — The enhanced cell proliferation, however, ceases after a few days even if treatment is continued.
It is considered that an effective feedback mechanism checkpoint function such as G1 or G2 arrest in cell cycle may prevent excessive cell multiplication in the normal liver even if the growth stimulatory signals are steadily present due to continuous chemical treatment It has been postulated that non-genotoxic chemicals with mitogenic activity may provide a selective growth advantage to spontaneously initiated precancerous cells over normal hepatocytes and lead them to neoplasms 28 , The increases in the number and size of eosinophilic AHF in our 2-year study could be a reflection of the mitogenic activity of DDT that contributes to the growth of initiated cells.
GJIC in the liver has been shown to be inhibited by various non-genotoxic tumor-promoting agents including phenobarbital and DDT in vivo and in vitro 14 , 18 — 20 , 22 , 32 — The inhibition of GJIC by tumor promoters may be produced in several ways Since DDT is highly lipophilic and accumulates in cell membranes, it could interfere directly with the function of GJIC, whereas phenobarbital which is not highly lipophilic may inhibit GJIC in a different way.
It is known that GJIC involves the passage of low molecular weight substances between adjacent cells via gap junctions and its function includes the possible regulation of cellular division through cell-to-cell exchange of replication signal molecules 19 , 34 , Therefore, inhibition of GJIC may isolate initiated cells from the growth regulatory signals of neighboring cells and permit the clonal expansion of initiated cells.
This suggests an important role for GJIC in the process of tumor formation. The liver weight also increased in correlation with duration of exposure but tended to reach a plateau after certain time. It is known that administration of mitogenic agents such as phenobarbital and buthylhydroxytoluene causes an increase in liver weight through mitogenic stimulation of cell proliferation Upon continued administration, the increased liver weight is maintained, even though the rate of cell turnover returns to normal levels The increased liver weights in the DDT-treated rats might be due to mitogenic stimulation of cell proliferation to some extent, but the major cause seems to be proliferation of smooth-surfaced endoplasmic reticulum SER associated with microsomal enzyme induction since the time of increase in liver weight and enzyme induction was consistent with each other during the study.
In our 2-year rat study, treatment with DDT induced centrilobular hepatocellular hypertrophy and increased eosinophilic AHF, hepatocellular adenomas and carcinomas Table After the use of DDT was discontinued in the United States, its concentration in the environment and animals has decreased, but because of its persistence, residues of concern from historical use still remain.
Since , EPA has been participating in international negotiations to control the use of DDT and other persistent organic pollutants used around the world. Under the auspices of the United Nations Environment Programme, countries joined together and negotiated a treaty to enact global bans or restrictions on persistent organic pollutants POPs , a group that includes DDT. The Convention includes a limited exemption for the use of DDT to control mosquitoes that transmit the microbe that causes malaria - a disease that still kills millions of people worldwide.
In September , the World Health Organization WHO declared its support for the indoor use of DDT in African countries where malaria remains a major health problem, citing that benefits of the pesticide outweigh the health and environmental risks. It is up to individual countries to decide whether or not to use DDT. EPA works with other agencies and countries to advise them on how DDT programs are developed and monitored, with the goal that DDT be used only within the context of programs referred to as Integrated Vector Management.
IVM is a decision-making process for use of resources to yield the best possible results in vector control, and that it be kept out of agricultural sectors. Skip to main content. Contact Us. Minus Related Pages. DDT exposure in people Exposure to DDT in people likely occurs from eating foods, including meat, fish, and dairy products. A small portion of the population had measurable DDT. Most of the population had detectable DDE. Links with this icon indicate that you are leaving the CDC website.
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