THE TROUBLING BENZENE RING – Its impact on health, crops, drug development, environmental policy-making and the therapeutic challenge
Beldeu Singh
Key words : occupational health, gender-bending compounds, haze, pollutant, dioxins, benzene, toxic air-contaminant, cumulative exposure, genotoxic, chromosomal aberrations, cancers, immune suppression, mitochondrial disease, benzene toxicity, metformin, POPs, phenolic metabolites, phenoxy radical, mitochondrial dysfunction, diabetes, diabetic wounds, phytochemicals, safe removal.
Abstract
Thirty years ago medical practitioners were naive about the conversion of drugs into metabolites in cells and their capacity to generate free radicals. The health authorities approved drugs for use in therapy and later the long term studies showed their side effects produced by their toxic metabolites. Antibiotics bind to plasma proteins and deplete minerals and antioxidants in the body. Steroids tend to promote fungal proliferation. Many drugs are immuno-suppressive. Now there is a whole new field of drug-induced illnesses. As chemicals were developed, their use spread and they entered the ecology, the food chain and ended up in blood or human breast milk, including dioxins and chemicals that have a gender-bending effect in boys. Compounds with the benzene ring are one of the most troubling due to the use of benzene in industry and medicine. It is a known carcinogen. Benzene in particular is immunosuppressive and toxic to genetic molecules even at very low levels of exposure. Natural sources of benzene include volcanoes and forest fires that create haze. Benzene and its derivatives produce detrimental effects through various mechanisms including through the formation of benzene metabolites that generate superoxide, the phenoxy radical and benzene-drug binding. Many drugs have at least one benzene ring in their chemical structure. Benzene metabolites bind to intracellular membranes where they cause degenerative changes and are different from non-benzene chemical metabolites that are lipophilic in nature and bind to cellular membranes. Degenerative changes in mitochondria leading to mitochondrial dysfunction are associated in many disease conditions. Public policy to control emissions and atmospheric concentrations or concentrations of circulating toxic metabolites alone is insufficient and incomplete without action to systematically remove them from the environment and to develop non-toxic interventions to safely remove them from the body. Public policies are weak due to economic pressures from industry and ignorance among politicians and law makers on the impact of pollutants and chemicals, including benzene and toxic metabolites on public health. The American society is the largest consumer of drugs and now, in many places, their tap water contains traces of up to 56 drug metabolites. And this will increase in the years ahead. New studies are required to understand the potential problem due to "cocktail effects" from different drug metabolites in drinking water. This is all the more necessary because all male roach sampled have been feminized to varying degrees, in some English rivers containing high levels of estrogens. The presence of estrogens in the environment is already known to cause adverse effects on reproduction by interfering with the endocrine system. Some of the policies must be reviewed and updated in the light of new information on adverse effects of certain chemicals and their metabolites even at low levels of exposure. Of particular interest are the detrimental effects of benzene and its metabolites on genetic molecules and hormones and treatment costs and the logic of treating such problems with more drugs, many of which may contain at least one benzene ring due to its genotoxic property. Knowledge of the effects of xenobiotics on mitochondrial function has expanded to the point that chemical structure and properties can guide in anticipating medication-induced mitochondrial toxicity. The disruption of Ca2+ ion channels in mitochondria leading to ROS generation and cancers is elucidated as one of the mechanisms in mitochondrial disease conditions.
Introduction
Dioxin is an organic chemical that consists of a pair of benzene rings, two oxygen atoms and four chlorine atoms. The chemical commonly called DDT (dichlorodiphenyl trichloroethane) also has two benzene rings and contains chlorine atoms.
Chemical structure of DDT and its conversion to its metabolites DDE (left) and DDD (right). (Wikipedia)
DDT and dioxin share several characteristics:
1. Both DDT and dioxin are toxic even in small quantities.
2. These chemicals, including dioxins, do not degrade in the environment. They persist in the ecosystem upon release and enter biological systems as it enters the food chain through fish and drinking water.
3. Both dissolve and accumulate in fat. The body may create new fat cells for its bioaccumulation or it may accumulate in fat cells in the mammary gland from where it can pass on to babies through breast milk.
4. Both do not dissolve in water and are not broken down by bacteria. Consequently, they persist in the environment for long periods of time, making it a “persistent organic pollutant”.
5. Both can lead to an increased risk of heart disease and diabetes and both have carcinogenic potential while dioxins can cause reproductive and developmental problems and fetuses are highly susceptible to developmental defects.
6. DDT and DDE, like other organochlorines are chemically similar enough to estrogens to trigger hormonal responses in animals. Biphenols (PCBs) and some dioxins are also endocrine-disrupters as they inhibit estradiol cell-growth. Research has shown that exposure to DDT at levels used in malaria control might cause preterm birth and early weaning. Toxicological evidence shows endocrine-disrupting properties; human data also indicate possible disruption in semen quality, menstruation, gestational length and duration of lactation.1 Other studies document decreases in semen quality among men with high exposures, generally from indoor residual spraying (IRS).2
7. Persistent organic pollutants (POPs) are known to cause mitochondrial dysfunction and this can produce a host of clinical symptoms, including muscle wasting and insulin resistance which may be due to the lipophilic nature of these chemicals and their metabolites and their adhesion to membranes of mitochondria.3
DDT was sprayed liberally starting in the 1940s to control agricultural insects, malaria and visceral leishmaniasis. Paul Herman Mueller awarded the Nobel Prize in Physiology or Medicine "for his discovery of the high efficiency of DDT as a contact poison against several arthropods." It was banned in the 1960s because it accumulated in the fat of animals and destroyed their ability to reproduce. Its metabolite (DDE) levels in the eggs birds corresponded with thinner egg shells. China ceased production in 2007 and India is currently the largest consumer. Dioxin suffers from the same problem. It is now listed among “gender-bending” chemicals as well.
Over the last hundred years, sperm counts are falling and the incidence of breast cancers has been increasing. This observation coincides with the increasing number of chemicals produced by industry and their increasing use in daily products, especially in the last thirty years. In this regard, it is interesting to note that in the US, diabetes rates have increased in concordance with the national production of synthetic organic chemicals.4
A population-based study in Belgium found that diabetic patients had significantly increased serum levels of dioxins and coplanar polychlorinated biphenyls. In 2006, cross-sectional data from the 1999–2002 U.S. National Health and Examination Survey5 showed a strong correlation between serum concentration of POPs (especially organochlorine compounds) and diabetes. The association with serum levels of POPs was subsequently extended by the same group to insulin resistance,6 to the prevalence of metabolic syndrome7 and to abdominal obesity among non-diabetic adults8. POPs are lipophilic compounds that accumulate mainly in adipose tissue. It has been proposed that mitochondrial dysfunction could play an important role in chronic low-grade inflammation in adipose tissue, which is believed to represent a crucial mechanism in the development of type 2 diabetes.9 Since low concentrations of POPs can induce disease conditions, low concentrations of drug metabolites in drinking water may also precipitate health problems and research is urgently required to determine their effects at the cellular and molecular level and the association of their serum concentrations to mitochondrial dysfunction and disease conditions. This issue is of special interest in medical anthropology, therapeutic science and national policy-making.
Sperm counts are falling so fast that young men are less fertile than their grandfathers and fathers and produce only a third as much, proportionately, as hamsters. And gender-bending chemicals are increasingly being blamed. The blame for the mystery of the "lost boys": babies who should normally be male who have been born as feminized boys instead. The Danish government set out to find out how much contamination from gender-bending chemicals a two-year-old child was exposed to every day. It concluded that a child could be "at critical risk" from just a few exposures to high levels of the substances, such as from rubber clogs and imperiled by the amount absorbed from sources ranging from food to sunscreens.
The results built on earlier studies showing that British children have higher levels of gender-bending chemicals in their blood than their parents or grandparents. Indeed WWF (formerly the World Wildlife Fund), which commissioned the older research, warned that the chemicals were so widespread that "there is very little, if anything, individuals can do to prevent contamination of themselves and their families." Prominent among them are dioxins, PVC, flame retardants, phthalates (extensively used to soften plastics) and the now largely banned PCBs, one and a half million tons of which were used in countless products from paints to electrical equipment.
Young boys, like those in the Danish study, could end up producing less sperm and developing feminized behavior. Research at Rotterdam's Erasmus University found that boys whose mothers were exposed to PCBs and dioxins were more likely to play with dolls and tea sets and dress up in female clothes. That is not all. Evidently, these chemicals seem to be altering male-female ratios in society. A Canadian Indian community living on ancestral lands at the eastern tip of Lake Huron, hemmed in by one of the biggest agglomerations of chemical factories on earth, gives birth to twice as many girls as boys. It's the same observation for people around Seveso in Italy, an area contaminated with dioxins from a notorious accident in the 1970s, and among Russian pesticide workers. And there's more evidence from places as far apart as Israel and Taiwan, Brazil and the Arctic. There is recognition of risks from "anti-androgen" and "estrogen-like" substances and the EU wanted a regulatory approach to the use of so-called "gender-bender" compounds.10
“Feminization of the male roach, Rutilus rutilus, a freshwater, group-spawning fish, is widespread in English rivers; among the causative agents are natural and synthetic steroidal estrogens and chemicals that mimic estrogens. In feminized male roach, concentrations of the egg-yolk protein vitellogenin are elevated, sex steroid hormone dynamics are altered, and gonad development is disrupted (most notably, a female reproductive duct or developing eggs [oocytes] are present in the testis). In some English rivers containing high levels of estrogens, all male roach sampled have been feminized to varying degrees.”11 The presence of some compounds termed endocrine disrupting chemicals (EDCs) in the environment can cause adverse effects on reproduction by interfering with the endocrine system. In some cases, exposure to EDCs leads to the animal feminization and male fish may develop oocytes in testis12. Yet gender-bending chemicals are largely exempt from new EU regulations controlling hazardous chemicals. Britain, then under Tony Blair's premiership, was largely responsible for this – restricting their inclusion in the first draft of the legislation, and then causing even what was included to be watered down. Confidential documents show that it did so after pressure from George W Bush's administration that protested that US exports "could be impacted".13
Benzene – Widespread use in industry and hazardous effects on health
Let’s look at benzene. What is benzene? Benzene is a colorless liquid that evaporates into the air very quickly and has a sweet odor.
Benzene is widely used in industry ranking in the top 20 chemicals in terms of production volume. Some industries use benzene to make other chemicals which are used to make plastics, resins, and nylon and synthetic fibers. Benzene is also used to make some types of rubbers, plastics, lubricants, dyes, detergents, explosives, drugs, napalm and pesticides. Its toxicity in pesticides explains its lethal and destructive effects in cells that kill the pests. Natural sources of benzene include volcanoes and forest fires. After volcanic eruptions and in haze generated by forest fires, the atmosphere contains low levels of benzene. Benzene is also a natural part of crude oil, gasoline and cigarette smoke. A common source of significant benzene exposure over the long term is tobacco smoke. It is now used as an additive to motor fuel (1-2%), replacing lead. Benzene is thus also found in exhaust from motor vehicles and industrial emissions.
Benzene inhalation can cause many different symptoms because of the different mechanisms and because it is rapidly metabolized to yield radicals and metabolites that can accumulate in cells of the various organs including the brain, lungs, liver and kidneys and because benzene and its metabolites can bind to DNA. It includes rapid or irregular heartbeat, headaches, tremors, confusion unconsciousness and death. Eating foods or drinking beverages containing high levels of benzene can cause vomiting, irritation of the stomach, dizziness, sleepiness, convulsions, rapid or irregular heartbeat, resulting in anemia and excessive bleeding. Some women who breathed high levels of benzene for many months had irregular menstrual periods and a decrease in the size of their ovaries. Acute deaths from benzene exposure at high concentrations have been due to ventricular fibrillation caused by exertion and release of epinephrine. It can also affect the immune system, increasing the chance for infection.14
The Department of Health and Human Services (DHHS) has determined that benzene is a known human carcinogen.15 It affects growth and cell division. Animal studies have shown low birth weights, delayed bone formation and bone marrow damage when pregnant animals breathed benzene.
The major effect of benzene from long-term exposure is that it depletes antioxidants in the bloodstream especially vitamin C. Hence its major effect is observed on the blood. It can also cause excessive bleeding. Benzene causes harmful effects on the bone marrow and can interfere with red blood cell production leading to anemia. Benzene can affect the immune system in ways that suppress it, thereby increasing the chance for opportunistic infections. Its immune suppression includes blocking the maturation of white blood cells and NK cells that can seek and destroy abnormal cells such as cancer cells in the blood. Naturally leukemia is also associated with benzene. The first case reports of benzene-induced blood diseases date from 1897. The first report of benzene causing leukemia was published in 1928. The first epidemiologic study of benzene among Pliofilm rubber workers showing significantly increased risks of leukemia was published in 1977. Since then, many epidemiologic studies of benzene have been done, which establish benzene as a cause of various human hematologic cancers and diseases.