Dose-effect is the relationship between dose and the severity of harmful effect or the magnitude of effect in a specified proportion of the population.
Dose-effect relations are important in describing the relationship between hazard dose and harm for many types of adverse health outcomes. It means that dose-effect relationship indicates how sick people will be at diff dose levels.
It is important to note that any determined dose-effect relationship only applies to a specified proportion of the exposed population because some may show resistance.
Dose-response: This is the relationship between dose and the proportion of the exposed population experiencing a specific effect following exposure .There will be a family of dose-response relationships for an effect which is graded. Where a chemical has more than one effect, dose-response relations will need to be established for each effect separately
The relationship will vary depending on the characteristics of the exposed group as well as on the nature of the chemical. Individual characteristics such as age, size of body mass, metabolic rate, state of health and hypersensitivity to chemical substances may make a number of the exposed population more vulnerable to the lethal effects of a toxicant. It is possible to estimate the lethal dose of a chemical if the number of deaths occurring
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In an exposed population is known. For example, LD50 (lethal dose 50%) represents the dose of a substance that produces death in 50% of the population exposed to a toxicant.
For exposures administered via inhalation the LC50 or lethal concentration 50%, is computed. The LD50 provides an initial comparative index of toxic potency. It is often quoted on Safety Data Sheets (SDS), but it should be remembered that it is only a crude measure of acute toxic effects. It will tell nothing about chronic effects such as cancer.
There is a threshold to be exuded to make harm.
Dose - effect and dose - response relations provide fundamental scientific data relating health impairment to the dose of an agent, in terms of both severity of effect and the proportion of the exposed population to suffer harm. We need to know all of this information if we are to assess health risks from hazard exposures in the workplace. So to establish standards to limit these acceptable limits of exposure.
Both dose-effect and dose-response data is used in in controlling and regulating the allowable or allowable level of exposure in workplace.it will limit the amount or concentration of that chemical or agent. These numbers will be used in MSDS and regulatory standards to be enforced by the law in the workplace.
In 1977 the International Labour Organisation (ILO) recommended the adoption of the generic term Occupational Exposure Limit (OEL) for hygiene standards for airborne contaminants. Broadly, OELs belong to one of the following two categories:
1. Maximum allowable concentrations, it represents peak values that should not be exceeded. Time weighted averages however, take into account duration of exposure at each concentration incorporated into the average.
2. Time weighted average concentrations (TWA)
The American Conference of Governmental Industrial Hygienists (ACGIH) produces an annually updated list of Threshold Limit Values (TLVs). This is accepted worldwide. In Australia by (Safe work Australia) uses Exposure Standard (ES) in terms of TWA and STEL (Short Term Exposure Limit) and being updated regularly and available in the HSIS database on their website.
For carcinogens the very concept of a threshold is thrown into doubt since it can be argued on theoretical grounds that a single molecule of a carcinogen is all that is required to make one cell malignant.
The concept of 'acceptable risk' is central to the process of setting hygiene standards.
Once the scientific data relating dose or exposure to harm have been elaborated, decisions are required to establish the exposure level that can be accepted as hygiene standard .the community tolerates or accepts some degree of risk from the large number of chemicals in industry. It is clear that this level of risk is not an absolute and that what is acceptable to the owner of the workplace may be unacceptable to persons in the community and the workplace who bear this risk to health.
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The MTD generally is determined from sub-chronic, 90 day studies, as a dose which slightly (by about 10%) suppresses weight gain. The MTD is below a dose level that is either acutely toxic or shortens the lifespan of the animals, both of which could mask the appearance of a long latency cancer. The use of the MTD markedly increases the tumour incidence and improves the chances of detecting a statistically significant effect.
There are a number of criticisms levelled against the use of MTD in animal carcinogenesis testing, not the least of which is that the dose is not representative of the much lower exposure levels that might pertain in workplaces. Despite the criticisms of the use of the MTD it has not been possible to develop better testing protocols using more representative dosing schedules.
Animal testing for carcinogenicity is an extension of general chronic toxicity testing. It is usually conducted on rats and mice over a period of about 2 years, i.e., as lifetime studies till death or being scarified. Organs and tissues are examined for signs of cancerous changes and tumour development.
It can be argued that direct implantation may by-pass normal body defence mechanisms and so will be unrepresentative of human patterns of exposure. Such limitations of long-term animal toxicity testing are difficult to overcome.
An agent which is carcinogenic in 1% of an exposed population has the potential to result in suffering and death of very large numbers of workers. Nevertheless a tumour incidence rate of just 1% is difficult to pick up with animal testing. Consider a test using 100 experimental and 100 control rats. That's quite a lot of animals to test, feed and generally care for over a 2 year period. A 1% tumour rate would be expected to result in just one experimental animal getting cancer. It is immediately clear that statistically the test would be unable to demonstrate the carcinogenic potential of the chemical, because it would be impossible to determine if the one tumour had arisen by chance alone or as a result of chemical exposure. The problem could be overcome by having more animals in the study, say 1000 rats in each group. There are obvious practical difficulties with this approach so the alternative is to increase the dose. Thus, in practice, animal carcinogenicity testing involves using perhaps just two dose levels, the maximum tolerated dose (MTD) and half the MTD.
Animal testing for carcinogenesis is based on the assumption that a chemical shown to be carcinogenic in animals can be carcinogenic in humans. However, the relative insensitivity of animal testing means that the absence of a positive association with cancer cannot be taken to demonstrate definitively that the agent is not carcinogenic to humans.
In order to obtain statistically meaningful results from a manageable number of animals, high (maximum tolerated) doses are often employed, particularly in carcinogenesis testing.
However, these doses are generally unrepresentative of human exposures. Perhaps the greatest disadvantage of animal toxicology is that no animal species mimics precisely human characteristics of absorption, distribution, metabolism, elimination and tissue response. Further, human behaviour such as tobacco smoking and other life style factors, may cause interactions with the chemical under study. Nevertheless, if there are no human data available, animal testing may be the only way to obtain information on the toxic potential of many chemicals. In general, human dose-response relations correspond reasonably well with many animal models if dose is determined as weight of substance per unit of body surface area. Humans appear to be more vulnerable, by a factor of about 10, to the toxic effects of chemicals if dose-response relationships are determined on the basis of dose expressed as weight of substance per unit of body weight.
In any toxicological study animal species selection depends on:
ï‚• a knowledge of species biology and susceptibility to disease,
ï‚• the animal life span,
ï‚• ease of handling,
The test animals usually employed are rats and mice. They are easy to breed, they have a short lifespan of around 2 years, they are cheaper to house, feed and care for than larger mammals and they are small enough to be handled relatively easily. Some toxicology protocols may require dog studies to be conducted, since dog metabolic pathways are closer to human metabolism. However, the dog lifespan is around 15 years, which makes it more difficult to conduct studies on lifetime effects. It is clearly problematic to wait more than 15 years to find out a particular industrial chemical is a potent carcinogen and there are obvious practical difficulties in attempting to maintain experimental conditions over such a long period.
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Animal toxicology studies allow much greater control of experimental parameters.
Population characteristics can be very closely matched between experimental and
control groups and doses can be precisely regulated, although chemical agents may be
administered via routes that do not reflect typical patterns of human exposure.
Animal carcinogenicity bioassay can also predict the sites and the type of timers produced by tested agents in exposed human population. Like benzene, the study showed pulmonary tumours in animals, benzene exposure has been linked to lung cancer in exposed workers to benzene. Long term animal carcinocity bioassays can provide data that must be used for regulatory actions, particularly on the permissible limits.
The most important sources of airborne cadmium are smelters. Other sources of airborne cadmium include burning fossil fuels such as coal or oil and incineration of municipal waste such as plastics and nickel-cadmium batteries (which can be deposited as solid waste) (Sahmoun et al. 2005).
Cadmium may also escape into the air from iron and steel production facilities. It resides on soil then it finds its way to food chain. Certain plants, such as tobacco, rice, other cereal grains, potatoes, and other vegetables, take up cadmium from the soil. The principal factor determining how much cadmium is absorbed is the route of exposure. Once exposed, how much cadmium is absorbed depends on many factors like age, gender, smoking and nutritional status. (1)
Once in the lungs, from 10% to 50% of an inhaled dose is absorbed, depending on particle size, solubility of the specific cadmium compound inhaled, and duration of exposure (Jarup 2002). Absorption is least for large (greater than 10µm) and water-insoluble particles, and greatest for particles that are small (less than 0.1 µm) and water soluble. A high proportion of cadmium in cigarette smoke is absorbed because the cadmium particles found in that type of smoke are very small (ATSDR 1999).
Most orally ingested cadmium passes through the gastrointestinal tract unchanged as normal individuals absorb only about 6% of ingested cadmium, but up to 9% may be absorbed in those with iron deficiency (ATSDR 1999). Also, cadmium in water is more easily absorbed than cadmium in food (5% in water versus 2.5% in food) (IRIS 2006). The presence of elevated zinc or chromium in the diet decreases cadmium uptake.
Cadmium is found in breast milk and a small amount will enter the infant's body through breastfeeding. The amount of cadmium that can pass to the infant depends on how much exposure the mother may have had.
Absorption through the skin is not a significant route of cadmium entry; only about 0.5% of cadmium is absorbed by the skin (ATSDR 1999).
Exposure to lower levels of cadmium for a long time can also cause bones to become fragile and break easily.
Absorption and Accumulation of Cadmium
Depending on the route of exposure, cadmium has differing rates of absorption and varying health effects. Cadmium is a cumulative toxin because of its very long half-life. Its levels in the body increase over time because of its slow elimination. It accumulates chiefly in the liver and kidneys. However, it also accumulates in muscle and bone.
Excretion of Cadmium:
Cadmium is eliminated from the body primarily in urine. The rate of excretion is low, probably because cadmium remains tightly bound to metallothionein, MTN, which is almost completely reabsorbed in the renal tubules.
Harm of cadmium to body tissues and organs
Eating food or drinking water with very high cadmium levels severely irritates the stomach, leading to vomiting and diarrhoea, and sometimes death.
Eating lower levels of cadmium over a long period of time can lead to a build-up of cadmium in the kidneys. If the levels reach a high enough level, the cadmium in the kidney will cause kidney damage.
kidneys: The kidneys can be damaged with both acute high-dose but more commonly, long-term chronic exposures
Bone: The bone disease that occurs with above average chronic exposures is thought to be secondary to cadmium's effects on the kidney.
The lungs are a target organ in acute high-dose exposures to inhaled cadmium fumes.
Damage to the lungs and nasal cavity has been observed in animals exposed to cadmium.
Cancer Lung cancer has been found in some studies of workers exposed to cadmium in the air and studies of rats that breathed in cadmium.
Carcinogenicity (2): There is sufficient evidence that cadmium metal and a number of cadmium compounds, such as cadmium chloride, oxide, sulphate, and sulphide, are carcinogenic in animals. Increased rates of testicular, prostate, and lung cancer in animals have been described (Sahmoun et al., 2005; ATSDR, 1999).
An occupational study showed increased numbers of chromosomal aberrations in the lymphocytes of cadmium-exposed workers (NTP 2004).
Cadmium has been found to cause chromosomal damage in animal experiments with subcutaneous administration (ATSDR 1999).
Cadmium causes mutations, DNA strand breaks, chromosomal damage, cell transformation and impaired DNA repair in cultured mammalian cells (NTP 2004).
Cadmium is known to modulate gene expression and signal transduction (Waisberg et al. 2003).