Cancer Holistic Treatment

Do I Have Cancer

This ebook from medical practitioner and family doctor Dr. Parajuli gives you all of the signs and symptoms that you need to know in order to catch cancer in the very early stages and protect yourself from it. You don't have to worry about if you have cancer anymore, and better yet you don't have to spend thousands of dollars to make sure of that either! All it takes is a bit of knowledge and you are on your way! This book also teaches about other aspects of cancer patients, such as how to live with different kinds of cancer, how to prepare yourself mentally to accept this reality if it IS a reality for you, and how to deal with doctors and insurance companies. This book is easy to read and in PDF format, so you don't have to worry at all about reading it. Make it easy on yourself!

Do I Have Cancer Summary

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Author: Dr. Parajuli
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Repair capacity and cancer risk

The reduced capacity phenotypes exists at an incidence of at least 10 , it would be expected that at least 1 of the individuals in the population will exhibit a reduced capacity in two repair pathways. Such individuals, with reduced capacity to repair both bleomycin and BPDE induced damage, are observed. These individuals exhibit a higher risk (OR 30) of developing lung cancer77 and hepatocellular carcinoma90 than individuals with a reduced capacity in only one pathway (OR 5-7). Thus, the evidence supports the conclusion that DNA repair capacity is a highly heritable trait that is related to individual cancer risk.

Summary of genetic variation and cancer risk

Genetic variation as exemplified by cancer susceptibility alleles is a key element in determining an individual's risk of cancer even in the absence of the highly penetrant variant alleles observed in cancer families. Cancer susceptibility alleles, although increasing risk only a few fold, exist at polymorphic frequency and have the potential to have a major impact on the population incidence of cancer.72 This impact is in contrast to the generally rare cancer alleles, which have a major impact on risk for the affected individual but only limted impact of the population incidence. Note the use of the term alleles rather than genes. This reflects the growing realization that different variants, with different degrees of negative impact on normal protein expression or function, exist in these genes. That is, cancer alleles and susceptibility alleles are likely to exist at the same locus. Note also that the normal function of these cancer genes is to prevent cancer and that it is the...

Cigarette smoke carcinogens

Tobacco smoke and its condensate contain a complex mixture of over 3800 compounds of these 50 have been identified as being either animal or human carcinogens.9 Of the several carcinogens present in cigarette smoke, polycyclic aromatic hydrocarbons (PAHs) (e.g., benzo a pyrene or B a P) and the tobacco-specific nitrosamines (e.g., or NNK) appear to play a major role in inducing lung cancer.10 Other classes of chemicals such as aza-arenes, aromatic amines (e.g., 4-ami-nobiphenyl or 4-ABP), heterocyclic aromatic amines, aldehydes, miscellaneous organic compounds (e.g., 1,3-butadiene), and inorganic compounds (e.g., Ni, Cr) are also known to be carcinogenic.9,10 In addition, tobacco smoke contains volatile compounds (e.g., benzene) and radioelements (e.g., polo-nium-210) that may also play a role in its carcinogenicity.10 Cigarette smoke also contains free radicals capable of inducing oxidative DNA damage. For example, the tar phase contains stable free radicals, such as catechols,...

Metabolic activation of cigarette smoke carcinogens and DNA adduct formation

Several of the chemical carcinogens present in cigarette smoke are inactive per se and require metabolic activation (e.g., PAH). Biotransformation of these chemical carcinogens results in the formation of reactive electrophilic intermediates, which covalently bind to nucleophilic sites in DNA forming carcinogen DNA adducts.13 In a human lung, several of the PAH carcinogens are predominantly activated by cytochrome P4501A1 (CYP1A1) enzyme to their ultimate carcinogenic metabolites, such as diol epoxides which bind covalently to DNA forming bulky aromatic DNA adducts.14 For example, the major metabolic pathway of B a P involves its conversion to benzo a pyrene 7,8-diol-9,10-epoxide (BPDE) via B a P-7,8-diol by CYP1A1, CYP3A4, and epoxide hydrolase in a two-step reaction. BPDE is an ultimate carcinogenic Similarly, several reactive metabolites generated through metabolic activation of PAHs, N-nitrosamines and aromatic amines are capable of forming bulky DNA adducts.15 In addition to the...

Role of smokingrelated DNA adducts in lung cancer

DNA adducts represent the biologically effective dose, defined as the amount of carcinogen bound to DNA in either target tissue or a surrogate tissue taking into account the individual differences in absorption and metabolism of a carcinogen to its DNA reactive intermediate(s), detoxification of the reactive intermediates, and repair of DNA damage. DNA adduct formation is generally accepted as one of the key events in tumor initiation during chemical carcinogenesis.19 The biological potential of a given DNA adduct depends on its mutagenic potential, ability to be repaired, location within a target gene, and the nature of the target gene.20 For example, formation of BPDE-dG adducts in mutational hot spots of the p53 tumor suppressor gene in lung cancer patients substantiates the association between tobacco carcinogen-induced DNA damage and lung cancer.21 Total DNA adduct levels, and in some cases specific adducts, have been correlated with in vitro muta tions,2223 chromosomal...

Other DNA adducts other types of cancer

Monitoring of the sequence-specific formation of PAH-DNA adducts along the p53 gene has provided important clues as to the potential origin of G to T transversion mutations in human lung cancers. A similar case can be made for the involvement of sunlight-induced cyclobutane pyrimidine dimers and p53 mutations in human nonmelanoma skin tumors.89,111 Interestingly, the DNA base 5-methylcytosine also plays an important role in enhancing formation of DNA damage by sunlight although the mechanism is, of course, completely different from that of enhanced PAH adduct formation at methylated CpG sites.112 One other obvious example, where an exogenous agent has been clearly implicated in human carcinogenesis, is the connection between aflatoxin B1 and human liver cancer. Hepatocellular carcinomas from geographic areas of the world with high suspected food contamination by aflatoxin B1 carry a unique G to T transversion mutation signature at codon 249 of the p53 gene. LMPCR and terminal...

Toxicodynamic Modeling of cancerRelated Effects of chemicals and a Binary chemical mixture

A further example of biologically based toxicodynamic modeling is computer simulation of clonal growth of initiated liver cells in relation to carcinogenesis. The impetus of this research development came from the desire to finding a way to evaluate carcinogenic potentials of chemicals or chemical mixtures without going through the resource-intensive chronic cancer bioassays (Yang 1994, 1997 Yang et al. 2004). The experimental animal model used for this research development involved a modification of the medium-term initiation-promotion bioassay of Ito et al. (1989a, 1989b). It is an initiation-promotion assay of a relatively short duration, and the modification incorporated toxicokinetics into the experimental design. This protocol allows the evaluation of carcinogenic potential within 8 weeks by identification of hepatic pre-neoplastic foci expressing glutathione S-transferase placental form (GST-P) as an endpoint marker. The clonal growth model is based on the 2-stage model of...

Molecular epidemiological studies of aflatoxin and human liver cancer

HCC is one of the most common cancers worldwide, and there is a striking geographic variation in incidence. For example, in the People's Republic of China, HCC accounts for over 300,000 deaths annually, the third leading cause of cancer mortality.5 During the 1960s and 1970s, several epidemiolog-ical studies were conducted in Asia and Africa that showed there was an association between high aflatoxin exposure, estimated by sampling foodstuffs or by dietary questionnaires, and increased incidence of HCC.6 While these early studies could not account for additional factors such as hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, this information provided a strong motivation to further investigate the circumstantial relationship between aflatoxin ingestion and liver cancer incidence. There have been two major cohort studies to address the relationship of aflatoxin exposure to HCC incidence reported to date. The first comprises over 18,000 people in Shanghai from whom urine...

Biomarkers and liver cancer prevention

Several approaches can be considered for the prevention of liver cancer. A first approach is vaccination against HBV. Unfortunately, many people living in high-risk areas for liver cancer acquire the HBV infection before age three. Thus, an immunization program for total population protection would have to occur over several generations, provided that mutant strains of HBV do not arise, thereby eliminating the utility of current vaccines. Despite these problems, vaccination programs for HBV have been implemented in many areas of Africa and Asia. A second approach for cancer prevention would be the elimination of aflatoxin exposures. Primary prevention of aflatoxin exposures could be accomplished through large expenditures of resources for proper crop storage and handling however, this approach is not economically feasible in many areas of the world. Secondary prevention measures using chemopreventive agents, which block the activation and enhance the detoxification of AFB1 are being...

Developmental Effects and Cancer

The potential of phthalate esters to produce cancer following long-term exposure will be discussed below. Occasionally, questions arise about the potential to develop cancer following short-term exposure. Based on animal studies, liver cancer associated with exposure to some high-MW phthalates occurs only after prolonged exposure 45,51,52 .

Table 23 Types of cancers reported following exposure to benzene

The role of benzene in some of these cancers is controversial, see text for details. Lung cancer Lung cancer Some mortality studies on benzene exposure have identified individuals with lung cancer (Aksoy, 1985 Yin et al., 1989 Hayes et al., 1996 Yin et al., 1996). However, the relative risk of lung cancer from benzene exposure is difficult to distinguish from the risks associated with cigarette smoking.

Health Risk Calculations For Carcinogens

Perhaps the most disputed, but very important, aspect of determining the effects of a pollutant on human health is our attempt to estimate the increase in cancer risk in a population exposed to the pollutant at a specific concentration. We start with the standard approach of developing a dose-response curve, such as the one shown in Figure 10.1, by exposing an animal to increasing concentrations of pollutant. After a given time period days, months, or even a lifetime the animal is sacrificed and examined for signs of cancer development. In rare cases, human data are available, not from experiments, of course, but from legal, illegal, or in many cases accidental exposures to pollutants. The obvious problem with animal experiments is determining how nonhuman responses in exposure studies relate to human responses to the same pollutant. In most cases, we do not know but rather approximate the relationship. To complicate the situation further, dose-response experiments are conducted at...

Tamoxifen is a carcinogen

The antiestrogen tamoxifen is widely used as first-line endocrine therapy for breast cancer patients more than 500,000 women in the United States are currently being treated with this drug.5 A randomized clinical trial designed for healthy women at high risk of developing this disease showed that therapeutic doses of tamoxifen reduced the risk of invasive breast cancer by approximately 50 .6 Subsequently, tamoxifen was approved in 1998 for use as a chemopreventive agent. Unfortunately, the use of tamoxifen in breast cancer patients is associated with an increased risk of endometrial cancer.712 A similar observation was made during the breast cancer chemo-prevention trial.6 Tamoxifen is listed as a human carcinogen by the IARC.13 The cellular mechanism responsible for this carcinogenic effect has not been defined.1416 Since tamoxifen induces hepatocellular carcinomas in rats1719 and tamoxifen-DNA adducts have been detected in rat liver, 1420-22 it is possible that tamox-ifen or its...

Lung cancer incidence predisposition and environment

Lung cancer is the paradigm of an environmentally induced disease. It is estimated that there will be 169,400 new cases and an estimated 154,900 deaths accounting for 28 of cancer-related deaths in the United States in 2002.1 The prognosis for lung cancer remains poor, with a 13 overall 5-year relative survival rate. About 87 of the cancer cases are attributed to cigarette smoking and the relative risk for lung cancer in current smokers compared with those who have never smoked is up to 20-fold higher.2 However, fewer than 20 of the cigarette smokers develop lung cancer. In genetic epidemi-ological studies, which utilize twin comparisons, the effects of genetic and environmental factors on current smoking, smoking initiation, and smoking persistence have been estimated. One of the conclusions that may be drawn from these studies is that, for most individuals, the liability to become and remain a smoker is explained by additive genetic factors.3 It has been reported that smoking and...

Molecular epidemiology of human cancer and DNA adducts

The emerging field of molecular epidemiology is based on the detection of biological markers of human chronic disease with environmental components for the purpose of identifying its causes and outcomes.912 Identification of human carcinogens is considered most accurate when supported by cancer epidemiology data.13 The biomarkers used in the molecular epidemiology of human cancer include specific changes at the gene and chromosome level (polymorphisms, mutations and cytogenetic alterations), concentrations of potential carcinogens and or metabolites in cells, tissues and biological fluids, and levels of covalent carcinogenic adducts to proteins and to DNA.14 In certain cases changes found at the molecular level may give insights into possible origins of the disease.915 Development of a biomarker normally involves thorough laboratory characterization in order to recognize its utility for molecular epidemiological studies. The ultimate level of validation of a biomarker is achieved...

Malignant Neoplasms Cancer

Cancer is any malignant growth in the body. It is an uncontrolled multiplication of abnormal body cells. The cause of the various types of cancer is unknown, circumstantial, or unclear except for cigarette smoking and exposure to ionizing radiation. There does not appear to be a dosage or level of exposure to cigarette smoking or ionizing radiation below which there is no risk. Viruses, genetic background, poor health, and exposure to various agents in our air, water, food, drugs, and cosmetics are believed to contribute to the disease. Some environmental substances become carcinogenic only after metabolism within the body, and gene-environment interactions are believed to be crucial in determining an individual's risk to developing cancer from exposure to toxins.

Solutions Cancer And Other Chronic Diseases

Cancer Clusters Acute environmental illnesses constitute a minority of all health problems handled by specialists in environmental health. More frequently, chronic diseases are at issue. A particularly common perception or complaint coming to the attention of environmental health practitioners is the concern that a given community has an excessive number of cancer cases. Although the steps required have been clarified in recent years, much time and effort is required to address effectively these concerns (CDC 2005). The first step in evaluating such a complaint is to verify that the numbers of cases actually justify concern. The investigator first establishes the geographical and temporal boundaries (place and time) of concern about increased risk. The cancer cases that occur (observed cases) are compared with the expected numbers calculated by applying tumor type-, age-, and gender-specific rates from population-based cancer registries to the numbers of persons in the same age and...

DNA adducts as intermediate biomarkers of lung cancer A Tobacco carcinogeninduced bulky DNA adducts

The presence of smoking-related DNA adducts was first established in human placenta,39 and the lung and larynx of smokers.40-42 The principal target organs of tobacco smoke-induced respiratory tract carcinogenesis (lung, bronchus bronchial epithelium, and larynx) consistently exhibit high adduct levels in smokers, while adduct levels in these tissues are absent or low in nonsmokers.1536 Smoking-related DNA adducts have also been detected in other target and nontarget tissues, including kidney, bladder, esophagus, pancreas, ascending aorta, liver, and cervix.42-44 BPDE-dG adducts have also been detected by immunohistochemistry in human sperm and in embryos from smoking couples.45 shorter half-life of 8 h.55 Therefore, in those studies in which the WBC samples consisted mainly of short-lived granulocytes, the inability to detect differences in adduct levels between smokers and nonsmokers may have been because there was insufficient time to accumulate stable adducts in these cells....

Health Risk Calculations For Noncarcinogens

Threshold Pollutant

In considering the carcinogenic effects of chemicals, there is no threshold dose of a chemical to which an animal species can be exposed safely. In risk calculations for noncarcinogens, though, it is accepted that there is a threshold chemical concentration, below which the chemical is not harmful. These values are calculated by taking a population of animals, exposing them to increasing doses of the chemical, and observing health effects. A generic plot of such an experiment is shown in Figure 10.2, where the response is shown on the y-axis and the chemical concentration is on the x-axis. Note the presence of the threshold, which is essentially just an estimate. There are several important points on the plot that need to be mentioned. The first is the lowest-observed-effect level (LOEL not shown in Figure 10.2) which is lowest dose administered to the animal that results in a response (death or health effect). The next point is the no-observed-effect level (NOEL not shown in Figure...

Role of Pahdna adducts in human carcinogenesis

PAHs are products of incomplete pyrolysis of organic matter and are widespread in the environment.3839 Humans are largely exposed to complex mixtures of these compounds. Sizable amounts of PAHs are generated as a result of industrial coke and iron and other metal production. In addition, PAHs are found in combustion emissions of fuels, including diesel and biomass, in certain types of cooked food, and in tobacco smoke. It is believed that the largest concentrations of PAHs are inhaled by smokers with the mainstream smoke of cigarettes.4041 Smoking is considered to be the major cause of upper aerodigestive tract cancers including cancer of the lung.42 Lung cancer is a leading cause of cancer death for American women and men43 and is one of the most common types of cancer worldwide. Therefore, smoking-related PAHs are strongly implicated as agents responsible for initiation and development of lung cancer. Interestingly, recent work still does not ascribe a role of diesel engine exhaust...


A retrospective mortality study of 887 male and 874 female patients that were observed for an average of 11 years following official registration as Yusho victims found no significant increase in male deaths (79 observed, 66.13 expected) or female deaths (41 observed, 48.90 expected) from all causes (Kuratsune et al. 1987). Mortality for cancer at all sites, however, was significantly increased in males (33 observed, 15.51 expected, standardized mortality ratio SMR 2.13) based on Japanese national rates. This is attributable to significantly increased mortality from liver cancer (9 observed, 1.61 expected, SMR 5.89) and cancer of the lung, trachea, and bronchus (8 observed, 2.45 expected, SMR 3.26). The increased mortality from liver cancer remained statistically significant when based on local death rates (SMR 2.53) and when early liver cancer cases (those occurring


First classified as probably carcinogen for humans (class B2) by the US EPA in 1987 71 , aldrin and dieldrin were then described as ''not likely human carcinogen'' 72,73 , since reported epidemiologic studies showed no correlation between pesticide exposure and cancer 74,75 . POPs and PCBs contamination of the environment is suspected to be the cause of the increasing incidence of breast cancer in European countries 76 . DDT is classified by International Agency for Research on Cancer (IARC) as possibly carcinogenic to humans (group 2B) 30 . Dioxins are carcinogenic in several animal species 77 and humans, and increased risk of cancer has been demonstrated at exposure levels more than 100 times the normal intake of the general population 78 . Dioxins are classified as human carcinogenic by the IARC 79-81 and either ''carcinogenic to humans'' or ''likely to be a human carcinogen'' by EPA 35 . This is consistent with the observations of Bertazzi et al. 82,83 , showing an increase of...

F UV carcinogenesis

The role played by free radicals in carcinogenesis has been debated for many years. There is little doubt that carcinogenesis involves free radical events and changing these events can effect the rate if not the final outcome of carcinogenesis. However, it is not clear how or at what stage antioxidants or other agents that affect free radical processes interfere with carcinogenesis. This discussion will focus on the early phases of carcinogenesis. Skin tumors are a good example because they are largely due to UV radiation and the ROS-mediated processes caused by UV.42 UV-mediated tumor formation in rodents was studied by Black and colleagues in the 1970s under the basic premise that ROS are important mechanistically.43-46 They determined that a cholesterol epoxide formed by ROS intermediates was important in the carcinogenic process.43 They showed that UV-mediated tumor formation decreased significantly in animals fed a diet containing antioxidants (i.e., 1.2 ascorbate, 0.5 butylated...

Assessment of current status of biomarker research

Nevertheless, there are exemplary results with biomarkers that can be mentioned. A recent summary highlighted the success achieved with biomarkers of exposure to aflatoxin.7 A biologically plausible model based on adverse effects of aflatoxin bioadducts supports the strong epidemiological link between adduct level and risk of liver cancer. In both animal models and human studies, DNA adduct level correlates with known or estimated external dose of aflatoxin. A urinary metabolite of the aflatoxin DNA adduct has also been used effectively as a quantitative biomarker of exposure. In addition, large-scale epidemiological studies (cross-sectional, longitudinal, and case-control) have been carried out using these biomarkers. Prospective studies are also ongoing and biomarkers of aflatoxin exposure have been used to monitor efficacy of intervention during clinical trials of the drug oltipraz. The aflatoxin biomarker is a unique example of a well-developed and useful molecular biomarker of...

Perfluorinated organic substances

Perfluorinated compounds (PFCs) or perfluorinated organic substances (PFOS) are used in a wide variety of industrial applications 13 . As a consequence these compounds show a global distribution in the environment 14 . They have been detected not only in environmental samples and fish but also in human blood and liver, and in several wildlife species 15 . PFOS show persistence in the environment and some of them have been related to different carcinogenic actions, for example, perfluorooctanoic acid has been identified as a potent hepatocarcinogen in rodents 16 . Meanwhile PFOS have been recognized by the EFSA and concentration levels, contamination pathways and toxicological potency should be assessed in the food chain.

Surface Water Treatment Rule

Cancer risk liver effects Kidney liver nervous system effects Kidney liver blood cell nervous system effects Cancer risk liver circulatory effects Liver nervous system effects cancer risk Cancer risk liver kidney nervous system effects Kidney liver effects Nervous system liver circulatory effects Cancer risk liver effects Cancer risk neurologic liver effects kidney liver nervous system effects

Regulations and Phthalate Esters

Phthalate esters have undergone comprehensive risk assessments regarding virtually all aspects of environmental and human health under existing substances regulations in the US, Canada, the EU, and at the Organization for Economic Cooperation and Development (OECD) level. These risk assessments have used the extensive data that has been generated for phthalate esters. The results of the various risk assessments completed to date have led to varying conclusions ranging from no further information needed and or no need for further restrictions on use, to proposed requirements for some use-specific risk reduction measures. Some of the recent reviews include cancer classifications for DEHP and BBP by the International Agency for Research on Cancer, reviews of seven phthalate esters by an Expert Panel of the U.S. National Toxicology Program Center for the Evaluation for Risk to Human Reproduction, and review of DINP in children's toys by the U.S. Consumer Product Safety Commission Chronic...

Peptide and protein growth promoters

The use of growth promoters in food producing animals has been banned in many countries since 1988 31 . Thanks to harmonization efforts most of the EU member states are capable of detecting steroids and b-agonists at the required level, although large differences in specific analyte coverage still exist. Hormone criminality is believed to be linked with sports doping and to occur via international networks. As in sports doping it can be predicted that the abuse will shift from classical growth promoters such as steroids and b-agonists to peptides and proteins when the veterinary control of the former becomes more effective. Bovine and porcine somatotropin (bST and pST), the equivalents of human growth hormone, are 22 kDa proteins and commercially available as recombinant preparations. They are important endocrine factors influencing metabolic and somatogenic processes including growth, immune function, reproduction and lactation. Their species specificity implies low toxicity in...

The Nature Of The Problem

DDT, the chemical for which Carson is most noted for highlighting, was banned in the United States at the end of 1972, eight years after her untimely death from cancer. Although the DDT ban spread to many temperate countries, few tropical countries acceded to the ban, largely due to the pesticide's efficacy to control the spread of malaria and other insect-borne diseases. DDT has been shown to dissipate much more rapidly in tropical than temperate soils 12 . The mechanism for the latter is partly attributed to increased temperature-mediated volatility, but more importantly increased microbial biodegradation. The mechanisms underpinning chemical persistence in the environment are complex but are thought to be heavily influenced by the rarity of the chemical's structure and substituents.

Environmental health science for the next century

This risk management debate has often been conducted using political, economic, or social rhetoric. Yet the key determinant is the availability of valid and robust scientific methodology pertinent to understanding the etiology of disease. This methodology must first enable the necessary definition and surveillance of diseases caused by environmental factors. Then, it must be able to determine causes. Fortunately, the recent rapid advances in molecular biology and in other biologically relevant technologies provide the necessary tools to develop indicators of cause and effect relationships by starting first with the disease and working backward to the cause. Whether by fingerprinting specific patterns of DNA codons altered by a chemical carcinogen or by understanding the subtle alterations in the immune system underlying pulmonary asthma, our new biology provides an opportunity to understand causation.

Pollution Classifications

Mixed waste, a very difficult waste to treat, usually refers to organic and radioactive waste being present in the same waste product. Inorganic waste can be further broken down into nontoxic and toxic metals, metalloids, and nonmetals. Metal waste can be subdivided into heavy metals and transition metals. Toxic wastes can be grouped as carcinogens, terratogens, and mutagens (discussed in Chapter 10). Compounds that are subjects of heightened public awareness, such as PCBs, are divided out even further. Other wastes are listed as hazardous based solely on their origin from a specific industrial process (for example, metal plating wastes) or when a specific chemical is present in the waste stream (for example, the presence of PCBs). As you see, there are many ways to categorize or list a waste, and each country will have their own system for classifying pollutants.

New European Chemicals Policies

Chemicals of greatest concern based on their inherent characteristics (carcinogens, mutagens, reproductive hazards, persistence and bioaccumulative potential) would need to be specifically authorized for continued use by the appropriate agencies of the member states or by the European Union (Tickner and Geiser, 2003).

Debrisoquinesparteine oxidation CYP2D6

CYP2D6 is now known to metabolize more than 72 drugs19 but few environmental pollutants. Numerous epidemiological studies, associating the CYP2D6 allelic differences with toxicity and cancer, however, have been reported. MPTP (N- methyl-4-phenyl-1,1,3,6- tetra-hydropyridine, formed as a byproduct during the illegal drug synthesis of a meperidine analog), and similar addictive compounds, can cause Parkinsonian tremors in humans MPTP inhibits CYP2D6-mediated metabolism in vitro. Individuals having the PM phenotype also appear to have a twofold to 2.5-fold increased risk of developing Parkinson's disease. The EM phenotype appears to be correlated with an increased incidence of tumors in the bladder, liver, pharynx, and stomach, and especially in cigarette smoking-induced lung cancer. These data suggest that enhanced CYP2D6-mediated metabolism of one or more unknown dietary or other environmental agents over decades of life, i.e., formation of a reactive intermediate, might play a role in...

How Can Cdfs Affect My Health

We do not definitely know if CDFs caused cancer in any of the accidentally poisoned people. There are no cancer studies in animals that ate or breathed CDFs. One study found that CDFs alone did not cause skin cancer in animals when they were applied to the skin for several months. However, when researchers applied another carcinogen to the animals' skin before applying CDFs, skin cancer developed. Although skin cancer developed in these animals, the Department of Health and Human Services, the International Agency for Research on Cancer, and the Environmental Protection Agency have not classified the carcinogenicity of CDFs.

How Can Chlorophenols Affect My Health

One way to see if a chemical will hurt people is to learn how the chemical is absorbed, used, and released by the body for some chemicals, animal testing may be necessary. Animal testing may also be used to identify health effects such as cancer or birth defects. Without laboratory animals, scientists would lose a basic method to get information needed to make wise decisions to protect public health. Scientists have the responsibility to treat research animals with care and compassion. Laws today protect the welfare of research animals, and scientists must comply with strict animal care guidelines. One man who splashed pure 2,4-dichlorophenol on his arm and leg died shortly after the accident. Workers who made pesticides from chlorophenols and were exposed to chlorophenols as well as other chemicals through breathing and through the skin developed acne and mild injury to their livers. According to some studies, the risk of cancer was also slightly higher among workers who had made...

Cadmium toxicity and CDM

Cadmium (Cd++) is a trace metal that exists at high concentrations in cigarette smoke, contaminated fish, and food, water, and soil in certain contaminated regions around the world. Cd++ has been designated a Group I human carcinogen, and inhaled Cd++ has been linked with respiratory tumors. Epidemiological evidence suggests that Cd++ exposure in humans might lead to testicular tumors, renal and pulmonary toxicity, and possibly osteoporosis. Striking interindividual variations have been found among people from the same area, same age group, and presumed to be exposed to the same amounts of Cd++.31 These findings suggest allelic differences probably exist in one or more human genes involved in relative sensitivity or resistance to heavy metal toxicity.

How Can Hccpd Affect My Health

One way to see if a chemical will hurt people is to learn how the chemical is absorbed, used, and released by the body for some chemicals, animal testing may be necessary. Animal testing may also be used to identify health effects such as cancer or birth defects. Without laboratory animals, scientists would lose a basic method to get information needed to make wise decisions to protect public health. Scientists have the responsibility to treat research animals with care and compassion. Laws today protect the welfare of research animals, and scientists must comply with strict animal care guidelines. No information is available on whether HCCPD causes cancer in people. The Department of Health and Human Services (DHHS) has determined that HCCPD does not cause cancer in rats and mice under the conditions of the study conducted by the National Toxicology Program. The International Agency for Research on Cancer (IARC) has not evaluated HCCPD as a possible cancer-causing chemical. The EPA...

Environmental genomics applications and issues

The basic techniques used in environmental genomics have already been mentioned under pharmacogenomics. In the case of environmental genom-ics, the studies are more complex for several reasons. The association of a single chemical and a disease response may not be well-established. Even if it is, the genes involved have probably not been defined well. The latter problem is manifested in cancer, a multifactorial disease often of poorly established etiology. Second, numerous examples of interactions of genetic and environmental factors exist. Examples include the resistance of individuals with sickle cell hemoglobin trait to malaria, the resistance of individuals with a lack of CCR5 gene function to human immunodeficiency virus, and the genetic influence (genes not well characterized) on development of lung cancer from smoking. Another example presented by Yokoyama et al.24 deals with aldehyde dehy-drogenase (ALDH2), ethanol, and the risk of head and neck cancer. Homozy-gous poor...

Variation in DNA repair genes

Substitutions to be associated with reduced protein function. This screening effort provides a catalog of variants that are reagents for subsequent biochemical and molecular epidemiology studies to address questions of the relationship of genetic variation and cancer risk. This has been described as a genotype to phenotype approach for molecular epidemiology studies.

Extent of variation

In addition, because of the linearity of the steps in the repair process or pathway, different variants may have a similar impact on repair capacity. That is, different variants in a gene or variants in different genes in a pathway could be considered to be equivalent in terms of impact on individual susceptibility and cancer risk. The amount of variation and the complexity of the genotypes when considering a process or pathway rather than individual variants or genes present significant challenges for molecular epidemiology studies.

Discussion Of Health Effects By Route Of Exposure

To help public health professionals and others address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure--inhalation, oral, and dermal and then by health effect--death, systemic, immunological, neurological, reproductive, developmental, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure periods--acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more). Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of CDFs are indicated in Table 2.2.

Biomarkers of Exposure

Variation in biomarkers of exposure to chemical carcinogens has also been associated with genetic variation in the carcinogen metabolizing enzymes.22-27 The increase in adduct level associated with the XRCC3 241Met genotype was more marked in smokers with the NAT2-slow phenotype,119 emphasizing the interaction between metabolism or damage induction and repair capacity. The sum of these studies emphasizes the complexity of the role of genetic variation in the individual response to an exposure. These studies documenting a role for individuals differences in response to common exposures begins to provide plausible explanations for the observation that the level of cytogenetic damage in lymphocytes is a better predictor of individual cancer risk than it is an estimator of historical exposure.121, 122 This is consistent with the accumulating data indicating that the health consequences of exposure to environmental agents result from the interaction of dose and the genetic constitution of...

Biodegradation of Aromatic Amines

Aromatic amines formed from reductive decolorization of azo dyes, either by biotic or abiotic processes, are generally toxic and are known or suspected carcinogens (Ekici et al. 2001). Further, they may undergo transformations, when they are released into water bodies. These may be more or less toxic than the parent compounds. Thus, the total degradation of the products formed is the only solution for abating the toxicity of these xenobiotics. In this section, mineralization of aromatic amines under different red-ox conditions, is briefly discussed.

Fundamentals of Cyclodextrin Chemistry 221 Structure and Properties

On the toxicological point of view, none of the a-, P- and y-CD shows major harmful effects for human being (Szejtli 1982, 1996a). No mutagenic, teratogenic or carcinogenic effects have been observed. As a result, an increasing number of commercial products or processes involves native or modified CDs.

Health Effects of Chemicals

There are some health problems in this latter class which seem to have grown over the period of growth of the chemical industry. In particular, while most of the rise in cancer is attributable to the fact that we are living longer and therefore stand a greater chance of getting it, some increases in cancer cannot be totally thus explained. Cancers of concern include testicular cancer, which increased in incidence by 55 between 1979 and 1991 in England and Wales breast cancer, which has been estimated to have increased in incidence by 1 a year in the USA since the 1940s prostate cancer, which increased by 40 between 1979 and 1991 in England and Wales, though at least some of this increase is due to improved diagnosis, as well as longer life. There also seems to be a rise in asthma, and possibly in reproductive health problems additional to cancers. diet, including greatly increased consumption of soya, which contains powerful endocrine modulators, and increased consumption of coffee,...

Phenotypic studies methods A Epidemiologic methods 1 Study design

Phenotypic studies of DNA repair are cell-based assays that measure the response to in vitro damaging agents. The design of these studies is presented in Table 7.1. Most phenotypic studies are case control studies (n 12)4-6,8-9,1113,16-2o while one assessed families,7 one examined a cohort of subjects and cases who developed second primary cancers.10 Two were cohort Cancer Site Colorectal cancer Head and neck cancer Lung cancer Head and neck cancer Head and neck cancer Study Method, Ethnic Group Design Cancer Site No. Cases Controls Study Method, Ethnic Group Design Cancer Site No. Cases Controls Lung cancer Lung cancer All cancers All cancers Lung cancer Lung cancer cancer Lung cancer The source of controls is not usually described in detail. Controls are often obtained in a similar manner to the cases, either as a subset of a larger study or as a convenience sample. Sometimes, they are matched by age and sex or other characteristics that might be important to cancer susceptibiltiy,...

Genotyping studies methods A Epidemiologic methods

Cancer Site Head and neck cancer Lung cancer 288 292 Lung cancer Colorectal cancer Lung cancer Cancer Site cancer Esophageal cancer cancer Lung cancer Breast cancer breast cancer Lung cancer BCC Lung cancer Bladder cancer Bladder cancer Breast and or ovarian cancer Esophageal cancer Chinese cases living in the United States with Chinese controls living in China. One study29 used cadaveric transplant donors as controls, and one used friends of the cases.26 Several studies match for exposure (typically, studies on lung cancer match on smoking). The response rate was usually not reported although the study by Duell et al.25 reported an important difference in response rates between cases and controls.

Laboratory methods

Three studies used a relatively high-throughput genetic technology (Taqman or LightCycler).23 25 38 PCR-RFLP was the most frequently used method although one study used PCR SSCP with sequencing.45 Genotype-pheno-type correlation and cancer status were sought in one study,17 with a comparison between the HCRA assay and genotyping for XPD in lung cancer patients. Cases and controls with the wild genotype had the most proficient DNA repair capacity as measured by the host cell reactivation assay. One study compared PCR-RFLP and DHPLC,40 others compared RFLP or SSCP with sequencing in a subgroup.

Assessment of causality

Strength of association Phenotypic studies tend to have relatively high odds ratios (ORs). As the sample sizes are quite small, the variabilities of the assays are often not reported, the reliability most often not measured, and the populations generally subsets of larger and hospital-based studies the large estimates of effect (i.e.,, odds ratios) are common. Larger studies are needed to determine whether phenotypes of low DNA repair capacity do actually have such large effects. The cohort study should demonstrate the most reliable results as measurement of phenotype would be made prior to the development of disease. It should be noted that ORs vary widely with the referent group used. Phenotyping is generally expensive and time consuming. Therefore, studies that attempt to correlate phenotype and genotype in such a way that genotyping, which is far less time consuming and expensive, would be valuable. Only one study17 to date has correlated phenotype and genotype among cancer cases...

Function and mechanistic interactions

A great deal of progress has been made in developing methods for population-based study of DNA repair in the last several years however, there is room for much more progress in the future. Researchers are genotyping large numbers of subjects for newly identified repair gene polymorphisms and association studies are being carried out. Information on the function and mechanistic interactions of these genotypic alterations is urgently needed. New technologies are being developed rapidly. It may soon be possible to determine whether a small decrement in DNA repair capacity predisposes to cancer. Ultimately, measures of DNA repair capacity may be developed as viable biomarkers for human susceptibility to cancer and possibly other human disease.

Analysis of smokingrelated DNA adducts

With recent advances in analytical biochemistry techniques, DNA adducts have been detected and quantified in target and nontarget tissues or surrogate tissues of smokers using highly sensitive methods, such as immunoas-says, the 32P-postlabeling assay, and fluorescence assays, with detection limits of one adduct per 106-1010 normal nucleotides.30,31 Immunological methods such as competitive enzyme-linked immunosorbent assay (ELISA) require the development of antibodies to the specific adduct of interest. Several polyclonal and monoclonal antibodies are available which can be used in large population studies.30,31 However, some of these antibodies frequently cross react with structurally related DNA adducts formed by other carcinogens. For example, the antibody raised against BPDE-dG cross reacts with diol epoxide adducts of other PAH carcinogens. Recently, immu-noslotblot assays are becoming increasingly popular owing to their high sensitivity (detects one adduct in 108 nucleotides)...

Oxidative DNA damage in smokers

Cigarette smoke, which is a complex mixture of chemical carcinogens, also contains high levels of oxidants. These ROS generated from cigarette smoke can induce DNA single strand breaks in vitro61 as well as cause oxidative DNA damage in cultured human cells62,63 and are known to be involved in chemical carcinogenesis.64 Among the various forms of oxidative lesions, 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG) is the most abundant product of oxidative DNA damage and is a sensitive marker of free radical-mediated DNA damage.17 Formation of 8-oxodG in DNA has been shown to be associated with mutagenesis65,66 and carcinogenesis,67,68 and in several animal studies this oxidative lesion has been shown to be associated with the incidence of cancer.69-71 Urinary excretion of 8-oxodG has been used extensively as a noninvasive biomarker of oxidative DNA damage in humans in vivo.72 Cigarette smoking has also been shown to generate high levels of 8-oxodG, which is detected in urine.73 However,...

Metabolic polymorphisms

Inherited polymorphisms in phase I (CYP enzymes) and phase II (predominantly GSTM1) drug metabolizing enzymes have been suggested to contribute to DNA damage and cancer susceptibility of an individual and may contribute to interindividual differences following exposures to carcinogens or mutagens.83,95,96 Aromatic DNA adduct levels in lung tissue of cigarette smokers have been related to the presence of particular CYP1A1, GST M1, and GST P1 polymorphisms in smokers.8, 97 In the CYP1A1 gene (CYP1A1*1 or wt), which encodes for the P4501A1 enzyme involved in the metabolic activation of PAH carcinogens, an Mspl polymorphism in the 3' noncoding region (CYP1A1*2) and an Ile-Val polymorphism in exon 7 (CYP1A1*3 or m2) both of which are found predominantly in Japanese populations and rarely if at all in Caucasians as well as a CYP1A1*4 polymorphism specific to African-Americans, have been shown to be associated with increased risk of developing lung cancer in several studies.98 Higher levels...

The Cradleto Cradle Approach to Material Assessment and Product Design

Once a material's chemical ingredients have been identified, each ingredient is profiled based on the attributes listed in Table 5.3. The attribute set is used to provide a profile of a chemical's potential human and environmental health effects and the profile can be modified as new tests, data, and discoveries become available. Some of the data relating to the attributes of chemical ingredients are available from numerous lists, that is, federal and state regulatory lists, international classifications, lists of carcinogens (National Toxicology Program Report on Carcinogens, NTP International Agency for Research on Cancer Carcinogens, IARC U.S. EPA Integrated Risk Information System, IRIS American Conference

Mutagenic potential of dGN2tamoxifen DNA adducts

Among several tamoxifen-DNA adducts described above, the mutagenic potential of dG-N2-TAM were established using site-specific mutagenesis.51 dG-N2-TAM adducts promoted primarily G T transversions, along with small numbers of G A transitions (Table 9.1). Except for a trans-diastereoi-somer (fr-1) of dG-N2-TAM, mutational frequencies were 12.4-14.0 , slightly higher than that observed with dG-C8-AAF, a model chemical carcinogen.52 The mutagenic specificities were similar to those observed in primer extension reactions catalyzed by mammalian DNA polymerases on dG-N2-TAM-modified DNA templates53 and in the liver DNA of lambda lac transgenic rats.54 Thus, dG-N2-TAMs are mutagenic lesions in mammalian cells.

Detection of tamoxifenDNA adducts in human endometrium

32P-postlabeling combined with chromatography has been used to detect tamoxifen-DNA adducts in endometrial tissue.2325,55 However, conflicting evidence has been published regarding the detection of tamoxifen-DNA adducts in human tissues. Using a 32P-postlabelling-TLC technique, Car-michael and his colleagues failed to detect tamoxifen adducts in the endometrium of tamoxifen-treated patients.23 Applying a 32P-postlabeling HPLC analysis, Hemminki et al. detected a putative tamoxifen-induced adduct in endometrial tissues obtained from breast cancer patients 25 the level of tamoxifen adducts reported was 0.29-0.82 adducts 108 bases standard markers were not used. Also using a 32P-postlabeling-HPLC analysis, Carmichael et al.24 reported they were unable to reproduce the results of the study by Hemminki et al.25 with tamoxifen (Table 9.2). The level of tamoxifen adducts were 0.2-18.0 adducts 108 bases, reproducing the results described in our previous study with 32P-postlabeling-TLC.55 We...

Other antiestrogen drugs

Tamoxifen is a hepatocarcinogen in rats while toremifene, a chlorinated tamoxifen analog (Figure 9.2), is not.19,59 Although toremifene, like tamoxifen, has estrogenic effects on the human endometrium,60 the formation of toremifene-DNA adducts in the liver of rats was two-orders of magnitudes less than that of tamoxifen.19 Therefore, genotoxic effects of tamoxifen are thought to be involved in development of rat hepatocarcinoma. Toremifene has been used for breast cancer chemotherapy in the United States since 1998. Raloxifene (Figure 9.2), a selective estrogen response modifier, reduced the incidence of breast cancer in women at high risk of developing this disease.61 Unlike tamoxifen, raloxifene is unlikely to react with DNA due to the absence of the ethyl moiety and does not demonstrate proliferative effects on the uterus of postmenopausal women.62 The incidence of endometrial cancer was not increased in women enrolled in the raloxifene chemopreven-tive trial.61 In view of their...

Air pollution and health

It appears that more than 10 of the benzene used by society (33 M tonne yr-1) is ultimately lost to the atmosphere. High concentrations of benzene can be found in the air of cities and these concentrations may increase the number of cancers. Exposure is complicated by the importance of other sources of benzene to humans, for example tobacco smoke. Toluene (C6H5CH3 Fig. 3.4d) is another aromatic compound present in large concentrations in petrol. Toluene is less likely to be a carcinogen than benzene but it has some undesirable effects. Perhaps most importantly it reacts to form a PAN-type compound, peroxybenzoyl nitrate, which is a potent eye irritant. As emphasized in the previous section, particles have increasingly come to be seen as an important influence on the environmental health of modern populations. The fine PM-2.5 is able to penetrate through the respiratory system all the way to the alveoli. Normally particles are removed from the...

Mass spectrometry and other methods

Gas chromatography-mass spectrometry (GC-MS) offers both high sensitivity and specificity of damage detection. Adducts of PAH, nitrosamines, mal-ondialdehyde and oxidatively damaged bases have been measured in human samples by this technique. The high cost of necessary equipment has limited the use of GC-MS in human biomonitoring. Also, the thermal stability and volatility GC-MS requirements of the sample are not always met by carcinogen-adducted DNA.13 These limitations may be overcome by combining liquid chromatography electrospray ionization with mass spectrometry (LC ESI-MS) or tandem MS.79 LC ESI-MS MS is extremely useful for analysis of DNA adducts, which are not amenable to GC and derivatization owing to the presence of several adjacent polar functional groups.79 Another

Fungal Biodegradation of Polycyclic Compounds

Lignin- and manganese- peroxidases (known as MnP and LiP) (Hammel 1992) and laccases (Majcherczyk et al. 1998). One of the main roles of lignin-degrading enzymes is to attack lignin. The latter is a complex molecule containing different structures, rings and links between the rings. Ligninolytic enzymes are, therefore, non-specific and highly versatile in their biodegradation capabilities, which allow them to biodegrade many different molecules, such as PAHs. On the other hand, the cytochrome P-450 system is also found in mammals, where PAH degradation follows similar pathways as in fungi. The biodegradation products, with the cytochrome P-450 system, are mainly epoxides and dihydrodiols which may show carcinogenic properties. In theperodixase-linkedpathway, quinones are formed (Kennes and Lema 1994a), which are much less harmful. In many cases, these metabolites tend to accumulate as dead-end products.

Human Health Risk Assessment

Human health risk assessments have been performed for pyrethrins and pyr-ethroids by the United States Environmental Protection Agency (USEPA), other government regulatory agencies around the world and university researchers. The USEPA has found that dietary exposure to pyrethrins and pyrethroids is below reference doses 10,11,68,118 these results are supported by the current weight of evidence based on urinary metabolites (see section 3.8). Permethrin has been observed in animal models to be a carcinogen and the USEPA estimated the worst-case lifetime average daily exposure based on a tier 1 conservative model to be 0.117 mgkg day-1. This exposure does not result, however, in an increase in incidents of cancer to the general US population.10 One commonly overlooked use of pyrethrins and pyrethroids is with ultra-low volume (ULV) application techniques, which are applied from trucks, helicopters or airplanes and are used for the control of public health pests such as adult mosquitoes...

Risk Associated with Exposure to Pyridine

Pyridine is 5 ppm (16 mg m3) and a concentration of 3,600 ppm is immediately dangerous to life. A concentration of 10 ppm becomes objectionable to unaccustomed individual and a concentration above 5 ppm leads to olfactory fatigue. EPA regulates pyridine as a toxic waste under the Resource Conservation and Recovery Act (RCRA) a maximum pyridine concentration of 5.0 mg per litre of leachate is allowed using analysis determined by the Toxicity Characteristic Leaching Procedure. Pyridine is listed as a chemical known to the State of California to cause cancer under the safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65).

Future directions

The QPCR assay holds great promise for measuring DNA repair capacity and levels of endogenous DNA damage in human populations. However a number of questions remain about the use of the QPCR assay as well as others listed in Table 11.1 for the measurement of DNA damage in human populations. If endogenous DNA damage is 100-fold higher than xenobiotic damage, as has been suggested, then it is unclear whether the more infrequent lesions from exogenous chemicals pose a real threat to biological systems.19 Peripheral lymphocytes are often used as surrogate markers for DNA, but does this cell population serve as a good marker for DNA damage throughout the body More studies must be done in animals to compare levels of adducts in target tissue versus peripheral blood cells. Since cancer can take as long as 20 years to develop in humans following the initial injury, any study of persistent DNA adducts must take into account the biological half-life of these DNA adducts. Finally, molecular...

Characterization of the Toxic Organic Compounds

Exposure to chlorinated dioxins and dibenzofurans causes chloracne which is mostly seen on the cheeks, behind the cheeks, in the armpits and groin region. Chloracne persists for more than 10 years. Abnormal reproductive effects such as decreased testosterone, reduced sperm count, male feminization are seen among males while females experience decreased fertility, miscarriage and endometriosis. Other effects that result from exposure to chlorinated dioxins include immune suppression, liver enzyme changes, nervous system damage and thymus, spleen and bone marrow damage (Mandal 2005). Both PCBs and dioxins are known carcinogens (Fig. 13.2).

Applications of TK and TD Modeling in Risk Assessment

Improving risk assessment can possibly be attained from TK and TD modeling, where it is physically impossible or not practically or ethically feasible to make direct measurements. Biologically based modeling may allow for informed extrapolation (e.g., between species). The most obvious example related to infeasible direct testing is the ethical limitations of human toxicological studies. Most mixture toxicity considerations for humans can only be undertaken by extrapolation from data obtained in experiments on other species. Especially, (suspected) carcinogenic chemicals cannot be administered to humans, but toxicological endpoints and models can be based on data from surrogate species (e.g., rats) or gained from subjects that are exposed to these chemicals on a daily basis from their own consent (e.g., smoking) or after an accident (e.g., radioactivity). In wildlife toxicology, similar issues apply, as it is impossible or impractical to test protected organisms. Furthermore, TK TD...

Detoxification Studies

Bioremediation using microorganisms is very attractive option but it is not always the case, it might increase toxicity (van de Wiele et al. 2005). The measurement for toxicity after microbial treatment suggests whether we should take the microbe for bioremediation further. There are many techniques reported so far to measure the toxicity. Effect of toxicity can be many ways such as genotoxity, carcinogenesis, teratogenesis, mutagenesis and stress caused by toxicant on physological activity. Genotoxic effect can be measured by many ways such as comet assay, end labeling of DNA to visualize the nicking in DNA. For carcinogenesis studies, a comprehensive study is required to established relationship. For mutational effect one can choose Salmonella mutagenesis test. The physiological stress can be measured by many ways depending on type of stress such as metabolic, neuronal, reproductive stress etc. Some specific biochemical and cell based assays are very much popular due to rapid and...

Grouping of chromiuminduced spectra with others

Recently, we began to investigate the mutagenic activity of chromate, Cr(VI), a known human carcinogen. Although chromate had been found to be mutagenic in a variety of test systems,72 73 the mechanism of mutagenesis was less understood. There was evidence that chromate was reduced in the cell by glutathione and other cellular reducing agents, generating reactive intermediates that cause oxidative damage to DNA.74 75 It had also been demonstrated that Cr(III), the stable end product of intracellular reduction of chromate, bound tightly to DNA.48 76 We reasoned that the mutational mechanism could be revealed through an analysis of mutation spectra. For these studies we used both protocols outlined in Figure 13.2. First, we treated

Regulatory Authorities In Health

Communicable and certain noninfectious diseases can usually be regulated or brought under control. In the United States, the local or municipal (often at the county level) health department is the fundamental unit of health intervention and surveillance. A health department having a complete and competent staff to prevent or control diseases that affect individuals and animals is usually established for this purpose. The preventive and control measures conducted by a municipal health department might include supervision of water supply, wastewater, and solid wastes housing and the residential environment milk and food production and distribution stream pollution recreational areas, including camps, swimming pools, and beaches occupational health and accident prevention insects and rodents rural and resort sanitation air pollution noise radiological hazards hospitals, nursing homes, jails, schools, and other institutions medical clinics, maternal and child health services, school...

Toxic Compounds from Plastic

Plastic products and their production processes release numerous types of toxic compounds (Islam 2003). Table 8.2 shows the release of toxic compounds from plastics and their related effects. More than 70,000 synthetic chemicals and metals are currently commercially used in the U.S. The toxicity of most of these is unknown or incompletely studied. In humans, exposure to some may cause mutation, cancer, reproductive and developmental disorders, adverse neurological and immunological effects, and other injuries. Reproductive and developmental effects are a concern because of the important consequences for couples attempting to conceive and because exposure to certain substances during critical periods of fetal or infant development may have lifelong and even intergenerational effects. The industry responsible for creating raw plastic materials is by far the biggest user of listed chemicals, reportedly using nearly 270 million pounds in 1993 alone. Plastic materials and resins are the...

Future Perspectives

It is well known that bacteriophages have been successfully applied as therapeutic agents to treat many notorious bacterial pathogens. There are few reports in which phages have been applied in food and agriculture field to kill infectious bacterial pathogens. Traditional chemical disinfectants that are used in water treatment process can form by-products that are carcinogenic in nature. Besides, antimicrobials resistant bacterial strains are ever emerging that are showing resistance to traditional chemical disinfectants. Therefore, now this is the time to think of an alternative antibacterial strategy. It seems possible that phages can be used in environmental problems especially in case of water borne epidemic diseases where it is difficult to control the pathogenic bacteria sources by chemicals. There are very few reports in which bacteriophages have been used as disinfectant in water bodies to kill bacterial pathogens. Bacteriophages could be applied as disinfectant to overhead...

Skin Damage from Sunlight

The ultraviolet light in sunlight can injure the skin and cause skin cancer (melanoma), depending on the exposure. Melanoma appears as a pigmented mole or tumor that may or may not be malignant. Melanomas are almost always curable if detected early and can be usually removed by surgery or freezing with liquid nitrogen. Cataracts can also result from too much sun.

Molecular responses of mammalian cells to nickel and chromate exposure

Abstract Previous studies from our laboratory have developed biomarkers to assess exposure and early toxicological effects to hexavalent chromium (Cr). Hexavalent Cr reacts with the phosphate backbone of DNA forming ternary complexes of protein Cr DNA, as well as glutathione and amino acid crosslinks with DNA. Recently, we have utilized the Uvr-ABC system and ligation mediated PCR to study and detect Cr DNA adducts in exon 5 and 7 of the p53 gene in human A549 cells. Preliminary results suggest that this technique can detect and map the sites of Cr DNA adducts at a single nucleotide level in exon 5 and 7 of the p53 gene. Interestingly, some of these sites appear to be at hotspots for p53 mutations in human cancer. We are also investigating whether Cr DNA adducts that were tightly bound to the DNA form these coordinate covalent bonds preferentially at guanines that are neighbored by methylated cytosines since previous studies have suggested that guanines near methylated cytosines are...

Biomarkers of chromate exposure

Humans are exposed to two major oxidation states of Cr, Cr(III) and Cr(VI).1 Cr(VI) is the most toxic and carcinogenic form of Cr. The high toxicity of Cr(VI) results from its active accumulation into cells, whereas Cr(III) is much A second indicator of Cr(VI) exposure involves its adduction with DNA. In the cell, the hexavalent form of Cr is reduced to the trivalent form which actually binds to the phosphate backbone of DNA and can cause the formation of ternary complexes involving glutathione, amino acids such as cys-teine and histidine, and DNA.7 Cr(III) can also adduct protein to DNA forming ternary protein-Cr(III)-DNA complexes.89 There has been a substantial amount of work using the DNA-protein crosslinks induced by chromate in white blood cells of humans as a biomarker of chromate exposure and early toxic effects.1011 Recently, we have utilized a UvrABC system and ligation-mediated PCR to study and detect Cr-DNA adducts in exons 5 and 7 of the p53 gene in human A549 cells....

Oxidative state of Cr and toxicity

Exposure to hexavalent Cr compounds has been consistently found to be associated with an elevated incidence of respiratory cancers and other adverse health effects.3-5 Squamous cell carcinoma is the most prevalent form of lung cancer among Cr(VI)-exposed workers.6 The genotoxic potential of Cr(VI) has been confirmed in animal experiments and in several cell-based assays6a7 Inhalation of Cr(VI)-containing acid mists in electroplating industry leads to nasal septum ulceration and perforation, as well as impaired lung function such as decreased vital capacity and forced expiratory vol-ume.8 Other health consequences of exposure to Cr(VI) include pulmonary fibrosis, chronic bronchitis, emphysema, and bronchial asthma.9 Ingestion of Cr(VI) can result in the irritation of mucous membranes and, in severe cases, intestinal bleeding. High doses of Cr(VI) cause renal tubular necrosis and can be lethal. Animal studies have also detected teratogenic activity of Cr(VI).9a Cr(VI) is the second most...

Post Synthesis Procedures

ZnO quantum dots-chitosan folate carrier loaded with anticancer drug and prepared following a post synthesis method, has shown a drug loading efficiency of ca. 75 (Yuan et al. 2010). The hydrophobicity and the positive charged character of the chitosan have enhanced the stability of the quantum dots. An initial rapid drug release followed by a controlled process has been observed for anticancer drug-loaded ZnO quantum dots -chitosan folate carrier.

Human and Mammalian Toxicology

In cancer research the resource-intensive chronic cancer bioassays originally needed to evaluate carcinogenic potentials of chemicals or chemical mixtures has led to the development of computer simulation of clonal growth of initiated liver cells in relation to carcinogenesis. This model describes the process of carcinogenesis based on the 2-stage model with 2 critical rate-limiting steps 1) from normal to initiated cells and 2) from initiated cells to malignant states. Because this approach can incorporate relevant biological and kinetic information available, it usefully facilitates description of the carcinogenesis process with time-dependent values without the need for chronic exposures.

Analysis of chromium in biological samples

The toxicological significance of Cr measurements in erythrocytes remains unclear due to the lack of data about the cellular uptake of Cr(III) complexes with lipophilic ligands. Cr(III) complexes with amino acids can cross cell membranes although less readily than the carcinogenic Cr(VI) form.67 Published animal studies comparing the distribution of Cr between different compartments of the blood typically used commercial chro-mium(III) chloride that forms Cr(H2O)4Cl2+ ion in a freshly prepared solution. This is not a toxicologically important Cr(III) compound and, therefore, is highly desirable to examine environmentally relevant Cr(III)-aqua ions and dietary Cr(III) complexes with organic ligands. (See introduction (I) and section concerning dietary chromium.) Analysis of the Cr content of biological tissues is not a trivial task even when expensive instrumentation is available because contamination and background problems are frequently encountered. The development of background...

Chemical Hazard Assessment

In assessing risks posed by chemicals to the environment, there are certain characteristics that are commonly taken to be important. These parameters are persistence (P), the propensity for a substance to withstand degradation and therefore remain in the environment in an unchanged state for a prolonged period of time bioaccumulation (B), the propensity to build up in biota (through, for example, accumulation in fatty tissues) resulting in bioconcentration that can especially impact top predators and toxicity (T), resulting in measurable harm to organisms in the environment (normally measured in aquatic organisms). In addition, chemicals are considered to be of concern if they are carcinogenic (C), that is they cause neoplasms, or are muta-genic (M) with the ability to cause cancers or affect the heritable genetic material, or are toxic to reproduction (R), causing measurable impacts on reproductive function (e.g. fertility) or outcome (i.e. defects in offspring). validated through...

Children S Susceptibility

Komori 1990 Vieira et al. 1996 NRC 1993). Whether differences in xenobiotic metabolism make the child more or less susceptible also depend on whether the relevant enzymes are involved in activation of the parent compound to its toxic form or in detoxification. There may also be differences in excretion, particularly in the newborn who has a low glomerular filtration rate and has not developed efficient tubular secretion and resorption capacities (Altman and Dittmer 1974 West et al. 1948 NRC 1993). Children and adults may differ in their capacity to repair damage from chemical insults. Children also have a longer lifetime in which to express damage from chemicals this potential is particularly relevant to cancer.

Ingestion of Pollutants in Soil

Where CS is the pollutant concentration in the soil (mg kg), IR is the ingestion rate (mg soil day) suggested values (EPA, 1989c) 200mg day children 1-6 years old, 100mg day 6 years old , CF is a conversion factor (10-6kg mg), FI is the fraction of soil ingested from the polluted site (versus soil ingested from a nonpolluted site or playground this value varies based on population activity patterns), EF is the exposure frequency (365 days year), ED is the exposure duration years 70 years for a lifetime exposure, 30 years (national upper-bound time (90th percentile) at one residence), 9 years (national median time (50th percentile) at one residence , BW is the body weight 70 kg for an average adult, 16 kg for children aged 1 to 6 years (50th percentile) , and AT is the averaging time period over which the exposure is averaged, in days (for noncarcinogenic effects, this is equal to ED x 365 days year for carcinogenic effects, use 70 years x 365 days year) .

Safer Chemicals Within Reach

Sustainable chemical policies are being proposed at regional and national levels. Sweden's new chemical policy has the objective of a nontoxic environment. Here a variety of goals and strategies include the phase-out of the most harmful substances increasing the information of chemical content in products promoting more ecolabelling and product declarations using public procurement to stimulate the market for safer materials and establishing ongoing dialogs with companies in various sectors to move towards safer chemical use (Geiser and Tickner, 2003). The new draft European chemical policy is itself a paradigm shift in the way chemicals are regulated. The proposed legislation, called REACH, requires the registration, evaluation, and authorization of chemicals and requires companies to provide environmental and human health toxicity data. This reverses the onus of proof and effectively ensures that by the year 2012, all chemicals must be registered prior to marketing. Chemicals found...

Toxic Effect Without a Threshold

Two types of toxic response are commonly believed not to have a threshold below which the possibility of an adverse effect can be discounted mutagenicity and geno-toxic carcinogenicity. Clearly, the deliberate exposure of humans to chemicals with such properties would be unacceptable and, wherever possible, such chemical usage should be banned (with the obvious exception of a pharmaceutical where the balance between risk and potential clinical benefit might be such as to warrant its use). However, particularly in environmental situations, humans may be inadvertently or unavoidably exposed to chemical mutagens and genotoxic carcinogens (of either 'natural' or anthropogenic origin). In such cases, particularly in the USA, mathematical models are used to quantify the expected level of response using the results of highdose animal experiments to predict low-dose human exposure situations. Examples include Multi-hit, Weibull and multi-stage models, with the US Environmental Protection...

Childrens Susceptibility

Are proportionately larger (Altman and Dittmer 1974 Fomon 1966 Fomon et al. 1982 Owen and Brozek 1966 Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 1985 Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many xenobiotic-metabolizing enzymes have distinctive developmental patterns, and at various stages of growth and development, levels of particular enzymes may be higher or lower than those of adults sometimes unique enzymes may exist at particular developmental stages (Komori 1990 Leeder and Kearns 1997 NRC 1993 Vieira et al. 1996). Whether differences in xenobiotic metabolism make the child more or less susceptible also depends on whether the relevant enzymes are involved in activation of the parent compound to its toxic form or in detoxification. There may also be differences in excretion, particularly in the newborn who has a low glomerular filtration rate and has not developed efficient tubular...

Molecular Biology and Recombinant Enzymes

The search for sequence variations in genomic DNA has becomes quite important in the studies related to inherited diseases and genes related to development of cancer. Different methods to detect DNA sequence variations have been developed during the past few years and one of these approaches are denaturing gradient gel electrophoresis (DGGE). This has been shown as quite sensitive method and thus has emerged as a choice in studying mutations in large genes. With respect to its application in the assessment of molecular diversity among the microbial populations, DGGE was carried out with five different primer sets targeting 16S rRNA gene of salt-tolerant alkaliphilic actinomycetes isolated from Coastal Gujarat (Western India), (Dalsaniya et al. 2009). The amplicon size of the isolates amplified with the same primer was quite similar, while it differed in size with other primer sets. It's quite apparent from these findings that DGGE generated valuable information on the group...

Quantitative evaluation of human exposure to mycotoxins

In humans the chronic toxicity of AFB1 is usually 3 linked to hepatocellular carcinoma (studies performed before 1980 in population from Thailand, Kenya, Mozambique and Swaziland). AFB1 is considered the most potent carcinogen of the aflatoxins The carcinogenicity of AFB1 is higher in people carrier of hepatitis B virus In animals carcinogenic to rodents nephrotoxic, neurotoxic, teratogenic and immunosuppressive activity In animals rodents, non-human primates and other 93,94 animal species fed with FB1-contaminated diets demonstrated the toxic effect in the liver and kidney. In horses and other equids, equine leukoencephalomalacia (ELEM) In humans the consumption of FBs contaminated corn 95,96 has been correlated with oesophageal cancer in regions of South Africa and China even if it does not subsist yet a confirmation of a direct implication considered as a cofactor in the high incidence of liver cancer in China Risk factor for neural tube defects in South Africa, 94 China and in...

Interactions With Other Substances

Data regarding the interaction of chlorophenols with other chemical substances in humans or animals were not located. Substances that result in effects similar to those for the chlorophenols have the potential to interact with these compounds. For example, chlorophenols may interact with other carcinogens, promoters, neurotoxic agents, and liver, renal, dermatologic, and ocular toxins. Factors interfering with Phase II conjugation reactions would inhibit the detoxification of chlorophenols. The results of recent experimentation indicate that the polycyclic aromatic hydrocarbon (PAH), 3-methylcholanthrene (3-MC), stimulates the glucuronidation of phenolic substrates through the induction of glucuronylsyltransferase (Jansen et al. 1992 Wishart 1978a, 1978b). The enzymes induced have a spectrophotometric peak of 448 nanometers (cytochrome P-448) and are characteristically distinct from the phenobarbital-type induced enzymes that have an absorbance maximum at 450 nanometers. These...

Mechanisms And Mixture Effects

How reliable are assumptions about mechanisms or modes of action in guiding choices between CA and IA as the appropriate assessment concepts Figure 3.1 shows an example with a mixture of anticancer drugs composed of agents with widely differing sites and modes of action. This diversity suggested that IA might provide a Figure 3.1 Combined effects of a combination of 7 anticancer drugs with different sites of action. Shown are the predicted (solid line concentration addition, broken line independent action), and the observed (circles) cytotoxic effects on DU 145 prostate cancer cells. Doxorubicin, daunorubicin, vincristin, cis-platin, etoposide, melphalan and 5-fluorouracil were combined at equitoxic concentrations. The mixture effect predictions were derived from the concentration-response curves of the individual anticancer drugs

Aflatoxin exposure and HBV infection in children

The use of biomarkers in cohort studies has clearly shown the chemical-viral interaction in the induction of HCC. However, aflatoxin exposure in the absence of chronic hepatitis B infection is also etiologically associated with liver cancer. These findings provide the compelling basis to increase efforts in HBV immunization programs and in the development of concerted programs to lower dietary aflatoxin exposure as means of lowering human cancer risk. These epidemiological studies have also compelled the case to understand if a mechanistic interaction between HBV infection and enhanced aflatoxin metabolism. Early studies in adults infected with HBV and exposed to aflatoxin showed no interaction between these two risk

The Need for Answers The Importance of Collaboration in Research

Thinking around how best to design a strategic research program so that the affected communities do not feel like guinea pigs. Guidry also commented on the added challenge created when messages are sent to the public about the potential chronic health consequences of exposure, such as cancer, despite insufficient scientific evidence to support those claims. He opined that sharing conjecture with the public may add to emerging mental health problems. Those messages can be difficult to hear when people are already worried about what they should and should not do in the face of a disaster. Williamson agreed with Guidry about the need to not let half-science create unnecessary fear. He said that part of the problem is that the longitudinal follow-up studies necessary to address some of the remaining questions about the potential long-term, human health consequences of exposure to oil spills were not conducted after the Exxon Valdez spill. He cautioned that the Deepwater Horizon disaster...

Pathways of Amines and Their Toxicity

Amines are considered to have negative environmental impacts. It was reported that occupational asthma was found in a patient handling a cutting fluid containing diethanolamine (DEA). DEA causes asthmatic airway obstruction at concentrations of 0.75 mg m3 and 1.0 mg m3 (Piipari et al. 1998). Toninello (2006) reported that the oxidation of amines appears to be carcinogenic. DEA also reversibly inhibits phosphatidylcholine synthesis by blocking choline uptake (Lehman-McKeeman and Gamsky 1999). Systemic toxicity occurs in many tissue types including the nervous system, liver, kidney, and blood system. Hartung et al. (1970) reported that inhalation by male rats of 6 ppm (25.8 mg m3) DEA vapor 8 hours day, 5 days week for 13 weeks resulted in depressed growth rates, increased lung and kidney weights, and even some mortality. Rats exposed continuously for 216 hours (nine days) to 25 ppm (108 mg m3) DEA showed increased liver and kidney weights and elevated blood urea nitrogen. Barbee and...

Biomarkers of Susceptibility

Biomarkers may be particularly useful in determining dose-response relationships, particularly if the biomarker can be measured at levels below which frank toxic responses can be confidently identified, and also potentially offer a means of facilitating cross-species extrapolations.28 When used in risk assessment, biomarker data may allow for the replacement or refinement of default assumptions used in risk assessments. For example, it has been estimated that the risk of cancer from dichloromethane may vary by, on average, 25 if differences in frequency of glutathione 6-transferase Type 1 genotype (GSTT1) are included using a combined Monte-Carlo simulation and physiologically based pharmacokinetic (PBPK) model.28 Use of validated biomarkers can facilitate biologically based risk assessments, but to date there are few examples of their application in quantitative assessments.28 Biomarkers of exposure and effect, in particular, can play an important role by informing the risk...

Applications of FISH

Since radiation is thought to cause equal levels of damage across all chromosomes,15 and chromosomes 1 through 6 (the largest chromosomes) make up 40 of the genome,16 it is hypothesized that measurement of damage in these large chromosomes can be extrapolated to the whole genome.11 This may not be true for chemical exposures as certain chemicals may have selective or preferential effects on certain chromosomes.17 For example, we showed that epoxide metabolites of 1,3-butadiene had more effect on certain chromosomes than others.18 Indeed, the hypothesis of equal levels of damage across the genome may not hold true even for low doses of radiation, as inversion of chromosome 10 has been shown to be highly sensitive to low intensity radiation exposure.19 Interestingly inv(10) rearranges the RET gene and is associated with thyroid cancer, potentially caused by linear energy transfer (LET) radiation. Our laboratory is currently employing FISH to examine the cytogenetic changes in human...

BTEX Benzene Toluene Ethyl Benzene Xylene

As they are suspected as being carcinogens, their release in the environment is strictly controlled and they are classified as priority environmental pollutants (An 2004) . BTEX compounds do not strongly adsorb to the soil therefore, they can reach groundwater and contaminate it (Langwaldt and Puhakka 2000). Important sources of water contamination are industrial wastewater and released petroleum products from storage tank, gas work sites, airports, paint manufacturer, chemical industries, and railway yard (Andreoni and Gianfreda 2007). BTEX compounds may comprise more than 50-60 by weight of the solubilized compounds when gasoline is introduced into water (Kermanshahi et al 2005 Farhadian et al. 2008). Permissible limits of BTX given by EPA (Environmental Protection Agency, USA) in potable water are 0.005, 1, and 10 ppm for benzene, toluene, and mixed xylenes, respectively (Farhadian et al. 2008) .

Conventional PCR detection of chromosome rearrangements

RT-PCR and PCR have previously been used to detect a number of translocations including t(14 18), t(8 21), t(9 22), and t(4 11). Using these techniques, t(9 22) and t(14 18) have been detected in unexposed individuals of different ages and in smokers.27-29 Both translocations were found to increase with age and the t(14 18) translocation was increased in cigarette smokers.30 Studies from our laboratory showing detectable t(8 21) by RT-PCR in an otherwise healthy benzene exposed worker20 clearly demonstrate the potential of RT-PCR for monitoring specific aberrations in populations exposed to suspected or established leukemogens. Because many of these translocations have multiple breakpoints or translocation partners, multiplex assays have also been developed to detect multiple or unknown rearrangements. Despite recent improvements in sensitivity and applicability, conventional PCR methods remain semiquantitative. However, with the recent advent of real-time PCR, quantitation is no...

Another potential application of realtime PCR measurement of aberrant gene methylation

In addition to the different types of genetic damage involved in carcinogen-esis, epigenetic mechanisms, such as DNA methylation, have gained attention as potential key players in certain cancer types. Aberrant methylation, which may be induced by environmental exposures, may result in altered carcinogen metabolism, cell cycle regulation, and DNA repair. For example, in leukemia and lymphoma, translocations cause the formation of novel fusion genes that produce excessive growth,37-38 and other genes undergo transcriptional silencing by methylation, which causes aberrant cell cycle control.39 Aberrant methylation and transcriptional silencing appears to be an early event in both solid tumors, including lung,40 colon,41 hepatocellular,42 and bladder,43 as well as hematologic malignancies.39 A number of different methods have been developed to detect aberrant methylation of genes, including the use of methylation sensitive restriction enzymes, bisulfite sequencing, and...

Chlorobenzene and Substituted Derivatives

A prevalent organochlorine insecticide, Lindane, is a chlorinated mixture of benzene which is termed as hexachlorocyclohexane (HCH). Lindane typically constitutes a, b, g and 8-isomer of HCH. They have been regarded as carcinogenic and listed in EPA priority list of pollutants (Phillips et al. 2005). Several bacterial strains were isolated for their ability to utilize HCHs as carbon and energy source (Senoo and Wada 1989 Sahu et al. 1990 Phillips et al. 2005). Lin pathway is regarded as major pathway for the aerobic metabolism of HCHs (Lal et al. 2010) in which HCHs are converted to maleylacetate and metabolized via b-ketoadipate pathway.

Joint Toxic Effect of Multicomponent Pollutant Mixtures

The third approach described here presents how and why a mixture of toxic and or carcinogenic compounds can exhibit greater impacts in the environment than the individual constituents themselves. Such an impact, called the joint toxic effect of multiple chemicals, has been recognized as an important consideration in environmental chemodynamics. An understanding of and ability to predict joint effects of chemical mixtures is beneficial to provide meaningful inputs in managing the environmental hazards of synthetic compounds. This prediction of mixture toxicity carcinogenicity can provide an insight about the bioavailable fraction of pollutants at aqueous-solid phase interfaces, and greatly enhance the decision-making processes in optimizing, limiting or preventing the disposal and or recycling of solid wastes until they meet certain environmental criteria.

Mobility and Bioavailability of Organic Pollutants Applications

This section represents different case studies to explain how physical and chemical properties, QSAR and QSPR approaches, and multicomponent toxic effect models can be used to predict the mobility and bioavailability of organic pollutants at aqueous-solid phase interfaces. Such interdisciplinary approaches are applied here to two groups of toxic and carcinogenic compounds.

Existing Information on Health Effects of HCCPD

As indicated in Figure 2-4, there are very few studies available on the health effects of HCCPD in humans. No studies were located regarding oral exposure. There are several reports of the effects of acute- or intermediate-duration inhalation and dermal exposure in the workplace (Kominsky et al. 1980 Morse et al. 1979). For the most part, these reports focused on systemic (respiratory, cardiovascular, gastrointestinal, hepatic, renal, dermal, and ocular) and neurological effects. Effects of HCCPD on human development, reproduction, genotoxicity, and cancer incidence have not been evaluated, although there have been studies of cancer incidence among workers involved in the manufacture of pesticides prepared from HCCPD (Shindell and Ulrich 1986 Wang and MacMahon 1979).

Identification of Data Needs

Occupational studies have typically involved individuals exposed to chlorophenols for intermediate- or chronic-duration periods. The results of these studies are described under the section Chronic-Duration Exposure and Cancer. Intermediate-duration oral administration of Chronic-Duration Exposure and Cancer. Dermal or inhalation exposure to the chlorophenols used in phenoxy herbicide production may be associated with cancer induction (Eriksson et al. 1981, 1990 Hardell et al. 1981 Hoar et al. 1986). Most investigators, however, have found only weak trends or no evidence of an association (Coggon et al. 1991 Kogevinas et al. 1992 Lynge 1985 Pearce et al. 1988 Smith et al. 1984 Woods et al. 1987). Many of the latter studies included a multinational cohort analysis of workers involved in similar production processes. Current experimental methodology is not sufficiently sensitive to determine those exposure factors, if any, that may be associated with the...