Intravenous exposure

Information on the distribution of absorbed americium to mammary milk in humans is not available however, maternal (oral or intravenous) exposures of animals, including cows and goats, have shown that... 

There is some evidence that nickel may have a role in the release of prolactin from the pituitary. In vitro studies have shown that nickel could directly inhibit the release of prolactin by the pituitary, and it has been suggested that nickel may be part of a prolactin inhibiting factor (LaBella et al. 1973). Intravenous exposure to nickel chloride has been shown to reduce semm levels of prolactin in male rats that were pretreated with chlorpromazine, which itself produces hyperprolactinemia (LaBella et al. 

The literature on potential toxic effects of di(2-ethylhexyl) phthalate following human exposure is limited. Taken together, the data indicate that di(2-ethylhexyl) phthalate does not cause observable toxicity following oral and intravenous exposure, but do not contribute information relevant to the evaluation of human carcinogenicity. 

Whole body retention studies in mice, rats, monkeys, and dogs following intravenous injection of radiolabeled silver nitrate indicate that silver excretion in these species follows a triexponential profile (Furchner et al. 1968). For mice and monkeys, this differs from the biexponential profile seen following oral exposure. Whole body clearance following intravenous exposure was slower than clearance following oral exposure in each of the four species observed. In addition, the difference in clearance rate between species was more dramatic. Clearance at 2 days post-exposure ranged from 15% in the dog to 82% in the mouse (see Table 2-5) (Furchner et al. 1968). 

The only information that exists regarding distribution of silver in humans comes from an accidental exposure to an unknown quantity of radiolabeled silver metal dust. The distribution of various silver compounds is known in animals following inhalation and intravenous exposure only qualitative information exists for oral or dermal exposure. Quantitative data on the distribution of various silver compounds following oral and dermal exposure would be useful when predicting the distribution of silver following exposure to specific silver compounds in humans. 

Cui, X., Kobayashi, Y Hayakawa, T. and Hirano, S. (2004) Arsenic speciation in bile and urine following oral and intravenous exposure to inorganic and organic arsenics in rats. Toxicological Sciences, 82(2), 478-87. 

Keys et al. (1999) note that certain model parameter values were estimated by applying a step-wise parameter optimization routine to data on blood or tissue levels following oral or intravenous exposure to DEHP and MEHP. The parameters estimated included the km and Vmax values for metabolism of DEHP and MEHP, and first order rate constants for the following parameters metabolism of DEHP (e.g., liver), absorption of DEHP and MEHP in the small intestine, intracellular-to-extracellular transfer of nonionized MEHP, and biliary transfer of MEHP from liver to small intestine (these values are not provided in the profile because they are derived from optimization procedures and might not be directly useful for other models). Keys et al. (1999) do not explicitly cite or describe the data sets used to optimize model parameter values, or distinguish the data used in optimization from data used in validation exercises. Based on Table 5 of their report, it appears that at least some data from Pollack et al. (1985b) were used to optimize the model. 

Other Systemic Effects. Other systemic effects have been observed. Barium sulfate was observed to act as an appendocolith in two cases following barium enema procedures (Palder and Dalessandri 1988). This is a rare occurrence and probably not significant in cases of human barium toxicity. Intravenous injection of barium sulfate into pigs increased calcitonin secretion from the thyroid (Pento 1979). This is probably not a significant effect for humans since intravenous exposure is not a common route and the dose required was so high (1.7 mg/kg/minute for 20 minutes) it caused cardiotoxicity. 

Domoic acid exposure to mammals occurs orally in a matrix of shellfish to human consumers, planktivorous fish and benthic invertebrates to marine mammals, and perhaps zooplankton and chained diatoms to whales. Analysis of the consumed mussels from the 1987 exposure indicated that 1 mg/kg was sufficient to induce gastrointestinal symptoms and 4.5 mg/kg could induce neurological effects in humans (Perl et al. 1990). Experimental studies in monkeys, rats and mice have utilized oral gavage, intraparenteal, and intravenous exposure routes and determined that oral gavage is about ten times less effective that the other routes of exposure (Iverson et al. 1990). Humans appear much more sensitive than either monkeys or rats, which when dosed orally have no observable adverse effect levels (NOAEL) at 5 and 28 mg/kg, respectively. Experimental animals have permitted evaluation of different dose scenarios. A daily NOAEL oral gavage of domoic acid to rats for... 

Dermal or intravenous exposure to lewisite leads to local skin edema and pulmonary edema due to increased capillary permeability. The increased capillary permeability results in blood plasma loss and resultant physiological responses collectively referred to as lewisite shock . Lewisite shock may be likened to shock observed in severe bum cases. It has been hypothesized that functional changes in the lungs, kidneys, respiratory tract, cardiovascular, and lymphatic systems may be the result of a disturbance of osmotic equilibrium (Goldman and Dacre, 1989). 

These data were quite variable, and thus could be due, at least in part, to a mass breakthrough of fibers that might be associated with the bolus intravenous exposure protocol. It is expected that transplacental transfer of fibers following environmental exposures (inhalation, oral, or dermal) to asbestos may be of a much smaller magnitude. 

The sera of 150 patients who had undergone cardiac surgery and were receiving aprotinin for the first time have been studied before and after the operation. At 3.5 months after surgery, the prevalence of aprotinin-specific IgG antibodies was 33% (15/45) after local, 28% (13/46) after intravenous, and 69% (41/59) after combined exposure (33). The authors concluded that local administration of aprotinin induces a specific immune response and reinforces that of intravenous exposure they therefore recommended that any exposure in a patient should be documented. 

Volatile anesthetics are administered exclusively via inhalation. Propofol is administered only intravenously. Exposure by other routes would not be anticipated. 

The very old and the very young are most susceptible to toxicity. Intravenous exposure results in a more rapid manifestation of symptoms, and toxicity is often iatrogenic. Even in therapeutic doses, parenteral administration may cause apnea and hypotension, especially with rapid administration of the drug. 

Different forms of lanthanide have different organ distribution and excretion rates. Intravenously injected chelated lanthanide is transiently accumulated in the kidney and most of the injected dose is excreted in the urine. However, intravenously injected soluble salt is taken up by the reticuloendothelial cells, with most of the dose accumulating in the liver and spleen. The result of this intravenous exposure is liver necrosis. 

Figure 5a and b illustrates the kinetics of a xenobiotic in blood resulting from repeated intravenous exposures. The time that is necessary to reach the steady state depends on the half-life of the xenobiotic and corresponds to about five times the half-life value, whereas the blood concentration is a function of the absorbed dose. 

The lowest published lethal dose after oral or intravenous administration in dogs was 25 or 14 mg kg respectively. Hypermotility, diarrhea, agranulocytosis, and body temperature decrease were shown after intravenous exposure. Similar effects were observed in monkeys. 

Oral absorption is rapid, with an absorption half-life of 7-11 min. Peak plasma levels occur at 45-60 min. The volume of distribution is highly variable, demonstrated to be 2.24 + 1 to 1.251 kg after oral administration but 0.261 kg after intravenous exposure. Yohimbine is excreted via the kidneys. Less than 1% of the unchanged drug was recovered in the urine after 24 h. Yohimbine is rapidly eliminated from the plasma with a half-life of less than 1 h. 

Llewellyn BM, Keller WC, Olson CT. 1986. Urinary metabohtes of hydrazine in male Fischer 344 rats following inhalation or intravenous exposure. AAMRL-TR-86-025. 

Developmental Effects. The developmental toxicity data for PAHs are mostly limited to in utero exposure of pregnant animals to benzo[a]pyrene via various routes of exposure. The placental transfer of benzo[a]pyrene has been shown in mice following oral and intravenous exposure of dams (Shendrikova and Aleksandrov 1974) and in rats after intratracheal administration (Srivastava et al. 

Rat bile and urine after oral or intravenous exposure to As compounds... 

If the clearance is plasma drug concentration-dependent, and either intravenous exposure is limited by blood stream solubility or the drug has very low bioavailability, there could be an error in the estimation of absolute bioavailability. For more on these PK parameters, see Chapter 3. Additionally, extravascular and intravenous administrations are performed at two different time periods any changes of metabolism in the study subject may also affect the calculated absolute bioavailability. 

In animal studies, nitrobenzene appears to be absorbed after dermal application based on observations of toxic responses in the treated animals. Shimkin (1939) reported that dermal painting of mice with liquid nitrobenzene (dose not stated) resulted in the death of most test animals after 1 to 3 applications. Dermal exposure of rabbits to nitrobenzene (dose not stated) for 22 to 205 days resulted in greater neural damage than did intravenous exposure (Matsumaru and Yoshida 1959). Administration of alcohol (not further identified) by stomach tube following exposure to nitrobenzene resulted in neurotoxicity by both routes of exposure. 

Strontium that has been absorbed from the gastrointestinal tract is excreted primarily in urine and feces. In two dial painters, rates of urinary and fecal excretion of radium approximately 10 years after the exposure were approximately 0.03 and 0.01% of the body burden, respectively (Wenger and Soucas 1975). The urine fecal excretion ratio of 3 that was observed in the radium dial workers is consistent with ratios of 2-4 observed several days to weeks after subjects received an intravenous injection of SrCl2 (Bishop et al. 1960 Blake et al. 1989a, 1989b Newton et al. 1990 Samachson 1966 Snyder et al. 1964 Uchiyama et al. 1973). Thus, urine appears to be the major route of excretion of absorbed strontium. The observation of fecal excretion of radioactive strontium weeks to decades after an oral exposure or over shorter time periods after an intravenous exposure suggests the existence of a mechanism for transfer of absorbed strontium into gastrointestinal tract, either from the bile or directly from the plasma. Evidence for direct secretion of strontium from the plasma into the intestine is provided by studies in animals (see Section 3.5.1). The available information does not address the extent to which biliary excretion may also contribute to fecal excretion of strontium. 

Intravenous exposure of seven dogs to 107 mg/kg ammonium acetate led to amounts ranging from 0.044 to 0.073 mg ammonia excreted in expired air. No measurable amount of ammonia was present in expired air during the pre-exposure control period (Robin et al. 1959). 

No studies were located regarding developmental effects in humans following intravenous exposure to mangafodipir. 

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