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It has been shown that specific antibodies can be produced in genetically engineered animals. Another example is to increase proteins that have physiological roles within the mammary gland itself such as -lactalbumin, 93 lysozyme, 94 95 96 lysostaphin 97 or other antimicrobial peptides. It is important to consider the use of transgenics to increase specific components, which are already present in milk for manufacturing purposes. This could increase the value of milk in manufacturing processes such as production of cheese or yogurt. One might also alter the physical properties of a protein such as -casein or -casein. Changes in other physical properties could result in dairy foods with improved characteristics, such as better tasting low fat cheese. This would also aid in manufacturing processes while also decreasing transportation costs for the more concentrated products in fluid milk. The end result would be more saleable product for the dairy producer and a reduced environmental footprint. The overall result of genetic engineering to modify milk will be the creation of more uses of milk and milk products in both agriculture and medicine. Enhancing Growth Rates and Carcass Composition the production of genetically engineered livestock has been instrumental in providing new insights into the mechanisms of gene action governing growth. This type of work enabled the study of chronic expression of these hormones on growth in mammals and fish. In addition, the production of these growth-enhanced salmon will have vast positive environmental benefits. Cutting in half the time required to raise salmon means supply can be increased without proportionately increasing the use of farms. In addition, land-based systems become economically viable and competitive with ocean-pen systems further reducing environmental impact. The apparent increase in food conversion rates means that fewer natural resources are required to produce the fish, thus enhancing sustainability. Certainly, there are numerous potential genes related to growth, including growth factors, receptors or modulators which have not yet been used, but may be of practical importance in producing genetically engineered livestock with increased growth rates and/or feed efficiencies. By changing the metabolism or uptake of cholesterol and/or fatty acids, the content of fat and cholesterol of meats, eggs and cheeses could be lowered. There is also the possibility of introducing beneficial fats such as the omega-3 fatty acids from fish or other animals into our livestock. Altering the fat or cholesterol composition of the carcass is another valuable benefit that can be delivered via genetic engineering. In: Proceedings of the Fifth World Congress Genet Applied to Livestock Production, Guelph, Canada 18:51-54. The use of genetic engineering to improve feed efficiency and/or appetite could profoundly impact livestock production and deliver significant benefits to producers, processors, and consumers. Increased uptake of nutrients in the digestive tract, by alteration of the enzyme profiles in the gut, could increase feed efficiency. The ability to introduce enzymes such as phytase or xylanase into the gut of species where they are not normally present, such as swine or poultry, is particularly attractive. The introduction of phytase would increase the bioavailability of phosphorus from phytic acid in corn and soy products. One group has reported the production of transgenic pigs expressing salivary phytase as early as seven days of age. Furthermore, transgenic pigs required almost no inorganic phosphorus supplementation to the diet to achieve normal growth. The use of phytase transgenic pigs in commercial pork production could result in significantly decreased environmental phosphorus pollution from livestock operations. Enhanced Animal Welfare through Improved Disease Resistance the impact of genetic engineering on animal welfare is compelling. Genetic engineering of agricultural animals has the potential to improve disease resistance by introducing specific genes into livestock. Many aspects of disease resistance or susceptibility in livestock that are genetically determined. Mastitis is an infectious disease of the mammary gland that causes decreased milk production and lost productivity.

While the assumption is frequently made that the toxic effects of multiple solvents are additive, solvents may also interact synergistically or antagonistically. Ethanol intake near the time of exposure to such solvents, in contrast, may competitively inhibit their metabolism and be protective. Another well-characterized example of solvent antagonism is the competitive metabolic interaction between benzene and toluene (Medinsky et al. Coexposure to these chemicals results in diminished benzene metabolism, genotoxicity, and erythropoietic toxicity relative to that which follows benzene exposure alone. It is now recognized that significant data gaps exist in the area of mixtures toxicology, and that these can be significant sources of uncertainty in risk assessments. Although some solvents are less hazardous than others, virtually all can cause adverse effects. Provided that the dose or concentration is sufficient, most have the potential to induce some level of narcosis and cause respiratory and mucous membrane irritation. A number of solvents are animal carcinogens, but only a handful have been classified as known human carcinogens. Herein lies a major challenge for toxicology-determining the human relevance of tumors observed in chronic, high-dose rodent studies. As with other chemicals, whether adverse health effects occur from solvent exposure is dependent on several factors: (1) toxicity of the solvent; (2) exposure route; (3) amount or rate of exposure; (4) duration of exposure; (5) individual susceptibility; and (6) interactions with other chemicals. Adverse health effects may occur acutely and be readily discernible, or they may be the result of chronic exposure and have insidious onset. Numerous epidemiologic studies of environmentally- and occupationally-exposed populations have been conducted for some solvents, but most human risk assessments remain heavily reliant upon extrapolation from high-dose animal studies. One must bear in mind that the toxic effects and their underlying mechanisms discussed herein may be operative only in certain animal species or strains and under certain exposure conditions. Care must therefore be taken in generalizing beyond the experimental conditions under which data are collected. While a relatively small number of commercially available solvents is discussed in this chapter, those selected for discussion are thought to best demonstrate principles of solvent toxicology, are of particular commercial importance, and/or are currently garnering significant attention from the toxicological and regulatory communities. A book chapter that examines solvents from an organ systems standpoint, in contrast to the discussion of individual solvents herein, is that of Gerr and Letz (1998). This syndrome was first described in the Scandinavian occupational literature in the late 1970s in solvent-exposed painters (Axelson et al. Since that time, numerous studies from Scandinavia have been published purporting that solvents as a class have chronic neurotoxic properties. These symptoms are reversible if exposure is discontinued, and there is no objective evidence of neuropsychiatric dysfunction. Sustained personality or mood change: There is a marked and sustained change in personality involving fatigue, emotional lability, impulse control, and general mood and motivation. Impairment in intellectual function: There is difficulty in concentration, impairment of memory, and a decrease in learning capacity. Dementia: In this condition, marked global deterioration in intellect and memory is often accompanied by neurologic signs and/or neuroradiologic findings. This condition is, at best, poorly reversible, but is generally nonprogressive once exposure has ceased. Type 2A Type 2B Type 3 source: Reproduced from Cranmer (1986), with permission from Elsevier. The categorization scheme that resulted from the Raleigh meeting is presented in Table 24-1. A major criticism of the categorization scheme is the lack of consideration of inhaled solvent concentration and exposure duration. Table 24-2 Functions that May Be Assessed in a Neuropsychological Evaluation Psychomotor functions Reaction time Motor speed and dexterity Eye-hand coordination Sustained attention/concentration and perceptual speed Verbal and nonverbal memory Immediate memory Delayed memory Learning Visual constructive ability Conceptual ability Evaluation of personality and affect source: Reproduced from Cranmer (1986), with permission from Elsevier. It has been argued that the neuropsychological tests are of questionable validity, sensitivity, specificity, and predictive value. The importance of doing so is best exemplified by the reanalysis of individuals originally reported in the seminal study by Arlien-Soborg et al. These reviews conclude that the current literature, including the "landmark" North American study of 187 paintmanufacturing workers (Bleecker et al. This does not preclude, however, the possibility that such exposure can be associated with subclinical cognitive dysfunction in the form of slight psychomotor and attentional deficit disorders. Their abuse has become a major drug problem worldwide, particularly in disadvantaged populations and among adolescents (Dinwiddie, 1994; Marelich, 1997).

They should also undergo the same standardized clinical, biological, or physiologic evaluation at the same time as the exposed group. Comparison with the general population is illadvised because an employed population is a highly selected group and may have a higher degree of physical fitness. Because occupational epidemiologic studies often last for several years, all methods of investigation-such as questionnaires, measurement instruments, and analytic techniques-must be validated and standardized before the start of the study. The number of subjects under study should be chosen based on a sample size calculation to be able to detect a difference between exposed and unexposed subjects (should there be a difference) and should take into account labor turnover and those declining participation in any aspects of the study. In most cases, occupational epidemiologic studies encompass the collection of samples from the subjects or data obtained through interaction with the subjects. Because this often includes identifiable private information, the confidentiality of the data must be protected. Rarely a combination by design Often doses studied are far higher than human exposures Measurement of administered dose with or without measurement of biomarkers Sampling of exposure chamber air for inhalation studies Laboratory animals, usually inbred strains of mice or rats Must ensure proper care and use of animals Experimental animal species may not represent humans Relevant if species differences are known Of limited relevance if species or strain effects on absorption, distribution, metabolism, and disease are unknown Control of genetics, feeding and housing between exposed and control groups Low variance in outcomes Frequency and duration Exposure route Appropriateness of dose Assessment Species considerations Representativeness Relevance to human health Analytical challenges Selection bias, misclassification, and confounding in characterization of outcomes Within- and between-subject variance may be high Animal Toxicology Testing for Establishing Acceptable Levels of Exposure It is evident that certainty as to the complete safety of a chemical can never be obtained, regardless of the extent of toxicologic investigations performed on animals. Nevertheless, animal studies provide valuable data from which to estimate the level of exposure at which the risk of health impairment is acceptable. Table 33-8 compares the information gained from animal studies to epidemiology studies. To the extent possible, animal studies should employ species for which the metabolic pathways and disease processes reflect those of humans. Guidelines and protocols for assessing experimentally the toxicologic hazards of chemicals have been formulated by various national and international agencies. These tests include local and systemic acute toxicity tests, tests of toxicity following repeated exposure, investigations of metabolism and mechanism of action, short-term tests for detecting potential mutagens and carcinogens, studies of effect on reproduction and of teratogenic activity, chronic studies to detect carcinogenesis and other long-term effects, interaction studies, tests for immunosuppression, and dermal and pulmonary hypersensitivity tests. The need for performing these testing protocols should be carefully evaluated for the inclusion of any occupational toxicant to which workers will be exposed. Conclusions drawn from any toxicologic investigation are useful only if the composition and physical state of the tested preparation is known. This would include the nature and concentration of impurities or degradation products, speciation of inorganic compounds, characterization of physical properties for inhaled materials, and characterization of the vehicle (if any). Sensitive and specific methods of analysis of the chemical in solution, air, and biological material should also be available. The assessment of the toxicity of malathion conducted in the 1970s illustrates this point. Malathion is an organophosphate insecticide that normally has relatively low human toxicity. This pesticide was responsible for a 1976 episode of mass poisoning among malaria workers in Pakistan because the specific product contained impurities (mainly isomalathion) capable of inhibiting tissue and plasma carboxyesterases (Baker et al. The toxicity evaluation for malathion had not anticipated isomalathion coexposure. The duration of tests necessary to establish an acceptable level for occupational exposure is primarily a function of the type of toxic action suspected. Subacute and short-term toxicity tests are usually performed to find out whether the compound exhibits immunotoxic properties and cumulative characteristics. They also aid in selection of the doses for long-term-exposure studies and the kind of tests that may be most informative when applied during long-term exposures. A number of studies have drawn attention to the fact that the reproductive system may also be the target organ of industrial chemicals (e. Thus, studies designed to evaluate reproductive effects and teratogenicity should also be considered during routine toxicologic testing of occupational toxicants. Information derived from exposure routes similar to those experienced by workers is clearly the most relevant. Experimental methodology is much more complicated for inhalation studies than for oral administration experiments and requires more specialized equipment and expertise (Thorne, 2000). For example, in the case of exposure to an aerosol, particle size distribution must be evaluated and the degree of retention in the respiratory tract of the animal species under study should be established. Ideally, particle size should be selected according to the deposition pattern of dry or liquid aerosols in the particular animal species used in order to represent human lung deposition with occupational exposures. Particle deposition and retention curves have been published for human, monkey, dog, guinea pig, rat, and mouse (Asgharian et al. Recent research coupling asymmetric multiple-path models of the bronchial tree and ventilation parameters can provide more accurate prediction of site-specific particle deposition (Asgharian and Price, 2006).

The condition most frequently manifests itself in the lungs (pulmonary tuberculosis - previously known as consumption), although it can affect tissues throughout the body. Bacteria inhaled into the lungs cause lesions, known as tubercles, in the lung tissue. At this stage, the immune system may fight off the infection, or it may lie dormant, to attack at some later time. Bloodstained sputum, severe fatigue, loss of appetite and weight, fever, and night sweats all then develop and worsen as the disease takes hold. Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease (such as jaundice), and indicates that the liver has sustained severe damage (loss of function of 80-90% of liver cells). The complications are hepatic encephalopathy and impaired protein synthesis (as measured by the levels of serum albumin and the prothrombin time in the blood). The degree of parenchymal inflammation is variable and is proportional to duration of disease. Zone 3 (centrilobular) occurs with ischemic injury, toxic effects, carbon tetrachloride exposure, or chloroform ingestion. Drugs such as acetaminophen may be metabolized in zone 1 to toxic compounds that cause necrosis on zone 3. The pathogenesis remains unclear but is likely to be a consequence of several phenomena. There is a build up of toxic substances like ammonia, mercaptan, endogenous benzodiazepines and serotonin/tryptophan in the brain. Autoregulation of cerebral blood flow is impaired and is associated with anaerobic glycolysis and oxidative stress. Neuronal cell astrocytes are susceptible to these changes and they swell up, resulting in increased intracranial pressure. Invasive intracranial pressure monitoring via subdural route is often recommended, however the risk of complications must be weighed against the possible benefit (1% fatal haemorrhage). The Liver has the central role in synthesis of almost all coagulation factors and some inhibitors of coagulation and fibrinolysis. Hepatocellular necrosis leads to impaired synthesis of many coagulation factors and their inhibitors. There is significant platelet dysfunction (with both quantitative and qualitative platelet defects). Progressive thrombocytopenia with loss of larger and more active platelet is almost universal. Because of impaired production of urea, blood urea does not represent degree of renal impairment. Impaired host defence mechanism, due to impaired opsonisation, chemotaxis and intracellular killing, substantially increases risk of sepsis. Bacterial sepsis mostly due to gram positive organisms and fungal sepsis are observed in up to 80% and 30% patients, respectively. Hypoglycaemia (due to depleted hepatic glycogen store and hyperinsulinaemia), hypokalaemia, hypophosphataemia and Metabolic alkalosis are often present, independent of renal function. Lactic acidosis occurs predominantly in paracetamol (also known as acetaminophen) overdose. Although delivery of oxygen to the tissues is adequate, there is a decrease in tissue oxygen uptake, resulting in tissue hypoxia and lactic acidosis. Pulmonary haemorrhage, pleural effusions, atelectasis, and intrapulmonary shunts also contribute to respiratory difficulty. From history and clinical examination, possibility of underlying chronic disease should be ruled out as it may require different management. A liver biopsy done via the transjugular route because of coagulopathy is not usually necessary, other than in occasional malignancies. Supportive treatment is with adequate nutrition, optimalisation of the fluid balance, mechanical ventilation and intracranial pressure monitoring (in severe encephalopathy), and treatment aimed at removing the underlying cause (such as acetylcysteine for paracetamol poisoning). While many people who develop acute liver failure recover with supportive treatment, liver transplantation is often required in people who continue to deteriorate or have adverse prognostic factors. Trey and Davidson introduced the term fulminant hepatic failure in 1970, which they described as a ". Terms subfulminant hepatic failure and late onset hepatic failure were coined for onset between 2 weeks to 3 months and for 8 weeks to 24 weeks, respectively.

Monitoring of the plasma or serum concentration at regular intervals will detect deviations from the average serum concentration, which, in turn, may suggest that one or more of these variables need to be identified and corrected. In a given patient, when the various factors are assumed to be constant, the administration of the same dose of a drug at regular intervals eventually produces a steady-state condition. Monitoring of steady-state drug concentrations assures that an effective concentration is present. For drugs that have a defined correlation between serum values and undesired toxic effects, the lowest serum value immediately prior to dosing (trough) and the highest expected serum concentration (peak) are monitored to assure efficacy and minimize toxicity. Appropriate situations for therapeutic drug monitoring are presented in Table 31-6. Because the drug being administered is known, qualitative characterization of the analyte generally is not required. Fundamental pharmacokinetic relationships for the repeated administration of drugs. The blue line is the pattern of drug accumulation during the repeated administration of a drug at intervals equal to its elimination half-time, when drug absorption is 10 times as rapid as elimination. As the relative rate of absorption increases, the concentration maxima approach 2 and minima approach 1 during steady state. The black line depicts the pattern during administration of equivalent dosage by continuous intravenous infusion. This metabolite has antiarrythmic activity of almost equal potency to that of the parent drug, procainamide. Because absolute characterization of the analyte is not necessary for many drugs, immunoassay procedures are commonly used. This is particularly true of drugs with extremely low serum concentrations, such as cardiac glycosides, and drugs that are difficult to extract because of a high degree of polarity, such as the aminoglycoside antibiotics. In these cases, serum can be conveniently assayed directly by using commercially available kits for immunoassays. The chromatographic methods in which an appropriate internal standard is added are favored when more than one analyte is to be measured or if metabolites with structures similar to those of the parent drugs must be distinguished. Because the nature of drugs is varied, many different analytic techniques may be applied, including atomic absorption spectrophotometry for measuring lithium used to treat manic disorders. Virtually, all the tools of the analyst may be used for specific applications of analytic toxicology. Drugs that are commonly monitored during therapy, their usual effective therapeutic serum concentrations, "panic values," and typical analytic methodologies applied to serum measurements are presented in Table 31-7. The term panic value denotes a serum drug concentration associated with the development of potentially serious toxicity. In clinical laboratories, the panic value alerts the toxicologist that the treating physician must be immediately contacted and notified of the test result. For example, methods that measure the parent drug and its metabolites are not ideal unless the individual analytes can be quantified separately. Depending on the drug, metabolites may or may not be active to a different degree than the parent drug. Often, environmental exposures are to a mixture of compounds and/or to compounds that are converted to physiologically important metabolites. Thus, analytic methods must be capable of separating a family of chemical agents and their major metabolites. Additionally, methods must be sufficiently specific and sensitive to measure minute concentrations of the compounds in complex biological matrices. An example of biological monitoring is presented in Table 31-8, which shows data relating to benzene exposure of chemists engaged in pesticide residue analysis in a state regulatory laboratory. Monitoring of the breathing zones at different locations around the laboratory where benzene was in use showed other concentrations of this material.