Insufficient Exposure

Historically, in vitro cytotoxicity tests have not been effective in predicting human toxicity potential [11]. This has been attributable largely to insufficiency of duration of 

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Is there sufficient systematic toxicity data available at levels that demonstrate adequate exposure If a study was designed such that there was insufficient exposure or duration of exposure to potential lymphoid target tissues, the test protocol may not be adequate to demonstrate an adverse effect. 

Dietary source required if insufficient exposure to UV light. Vitamin 1% is found in saltwater fish (salmon) and egg yolks. 

Renal insufficiency Exposure levels of other metabolites of tolterodine were significantly higher (10- to 30-fold) in renally impaired patients. 

Vitamin D3 is a precursor of the hormone 1,25-dihy-droxyvitamin D3. Vitamin D3 is essential for normal calcium and phosphorus metabolism. It is formed from 7-dehydrocholesterol by ultraviolet photolysis in the skin. Insufficient exposure to sunlight and absence of vitamin D3 in the diet leads to rickets, a condition characterized by weak, malformed bones. Vitamin D3 is inactive, but it is converted into an active compound by two hydroxylation reactions that occur in different organs. The first hydroxylation occurs in the liver, which produces 25-hydroxyvita-min D3, abbreviated 25(OH)D3 the second hydroxylation occurs in the kidney and gives rise to the active product 1,25-dihydroxy vitamin D3 24,25 (OH)2D3 (fig. 24.13). The hydroxylation at position 1 that occurs in the kidney is stimulated by parathyroid hormone (PTH), which is secreted from the parathyroid gland in response to low circulating levels of calcium. In the presence of adequate calcium, 25(OH)D3 is converted into an inactive metabolite, 24,25 (OH)2D3. The active derivative of vitamin D3 is considered a hormone because it is transported from the kidneys to target cells, where it binds to nuclear receptors that are analogous to those of typical steroid hormones. l,25(OH)2D3 stimulates calcium transport by intestinal cells and increases calcium uptake by osteoblasts (precursors of bone cells). 

Vitamin D deficiency remains the most common cause of rickets and osteomalacia in the world, with the exception of the United States and the Scandinavian countries where most dairy products are supplemented with this vitamin. This deficiency can be caused either by dietary habits or by insufficient exposure to ultraviolet light. The same type of symptoms can be observed when there is interruption of the normal vitamin D metabolic pathways due to a number of liver and/or kidney diseases. In addition, a number of inherited factors can lead to different types of vitamin D resistance which require massive supplements of vitamin D and/or minerals. Extensive reviews have been published depicting both the clinical features and their most likely causes, as well as the possible treatments of the different types of clinical disorders resulting from vitamin D deficiencies [113-117], The newly defined role for l,25(OH)2D3 upon the hematopoietic system could also have clinical relevance in bone disorders such as osteoporosis where patients have been shown to possess abnormal T-cell subsets [118]. 

One of the key disadvantages of non-covalent immobilization is the insufficient exposure of functional domains, largely due to a variety of unpredictable orientations that the immobilized molecules can adopt upon binding to the glass surface. This often results in immobilization of an unneces-... 

Cortisol-Cortisone Conversion. Under normal conditions, this equilibrium slightly favors the oxidized compound. Similarly, the conversion of corticosterone to 11-deoxycorticosterone is also mediated by the liP-hydroxysteroid dehydrogenase enzyme system and requites NAD(P) /NAD(P)H. This conversion is especially important both in the protection of the human fetus from excessive glucocorticoid exposure, and in the protection of distal nephron mineral ocorticoid receptors from glucocorticoid exposure (14). The impairment of this conversion is thought to result in hypertension associated with renal insufficiency (15). 

There is insufficient evidence to unequivocally link nitrosamine exposure to elevated risk for human cancer (159). There are, however, a number of specific cases, especially with respect to the tobacco-related nitrosamines, in which exposure to V/-nitroso compounds is of concern. The strongest evidence in this context is probably that relating to oral cancer rates among habitual users of smokeless tobacco (snuff). Oral cancer rates among this group are significantly elevated over those of nonusers, and /V-nitrosonornicotine, and 4-(methylnitrosamino)-l-(3-pyridinyl)-l-butanone [64091 -91 both of... 

The replacement of asbestos fibers by other fibrous materials has raised similar health issues in relation to substitute materials. However, since lung cancer has a latency period of approximately 25 years, and since the fiber exposure levels in contemporary industries is far lower than those which prevailed half a century ago, the epidemiological data on most substitutes is insufficient. A possible exception is slag fibers for which several studies on worker populations are available over extended periods (44) some results show a substantial increase in lung cancer occurrence. Consequentiy, the toxicity of asbestos substitute fibers remains a subject of active investigation. 

Prolonged contact with certain chromium compounds may produce allergic reactions and dermatitis in some individuals (114). The initial response is usually caused by exposure to Cr(VI) compounds, but once the allergy is estabUshed, it is extended to the trivalent compounds (111,115). There is also limited evidence of possible chromium associated occupational asthma, but there is insufficient data to estimate a dose for assumed chromium-induced asthma. Reference 116 provides a summary and discussion of chromium hypersensitivity. 

A WBL can also be formed within the silicone phase but near the surface and caused by insufficiently crosslinked adhesive. This may result from an interference of the cure chemistry by species on the surface of substrate. An example where incompatibility between the substrate and the cure system can exist is the moisture cure condensation system. Acetic acid is released during the cure, and for substrates like concrete, the acid may form water-soluble salts at the interface. These salts create a weak boundary layer that will induce failure on exposure to rain. The CDT of polyolefins illustrates the direct effect of surface pretreatment and subsequent formation of a WBL by degradation of the polymer surface [72,73]. 

However, there are substances for which an 8-hour OEL-TWA alone provides insufficient protection. In such cases the OEL-STEL is used in relation to a 15-minute period, unless otherwise specified, in order to prevent adverse health effects, immediate or delayed, due to peaks in exposure that cannot be ccmtrolled by the application of an 8-hour OEL-TWA. The OEL-STEL indicates a limit value above which exposure should not occur, and it is needed when there are recognized acute effects from a substance whose toxic effects are primarily of a chronic nature. 

In cases which recover from the pulmonary edema, there is usually no permanent disability, but pneumonia may develop later. Concns of 100—150ppm are dangerous for short exposures of 30 to 60 minutes. Concns of 200—700ppm may be fatal after even very short exposures Continued exposure to low concns of the fumes, insufficient to cause pulmonary edema, is said to result in chronic irritation of the respiratory tract, with cough, headache, loss of appetite, dyspepsia, corrosion of the teeth and gradual loss of strength... 

Although a number of studies have reported the effects of inhalation exposure to methyl parathion in humans, no inhalation MRLs were derived based on human data because of the lack of adequate quantitative exposure information. Animal data were also insufficient to support the derivation of an acute-, intermediate-, or chronic-duration inhalation MRL. 

There are insufficient data to determine potential daily inhalation and dermal exposure levels. However, based on the information presented in Seetions 6.3 and 6.4, exposure levels for the general population are probably very low by these routes. Inhalation exposure is not important for the general population, with the possible exception of those individuals living near areas where methyl parathion is frequently sprayed. Since methyl parathion is readily adsorbed through the skin, dermal eontact may be the most relevant exposure pathway. Dermal eontaet is most likely to oeeur in people who are occupationally exposed. 

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