Species variability

Different species react differently to chemicals. Chemicals that we consider safe may be toxic to other species. For example, dogs lack an enzyme needed to metabolize chocolate. Therefore, chocolate is toxic to dogs. Obviously it isn t to humans, or else the human race would be in big trouble Even for chemicals that are toxic to most species, there are tremendous differences in sensitivity of toxic effects across species. A great number of chemicals are used as pesticides, fungicides, herbicides, etc., precisely because these chemicals are more toxic to a weed or insect species than they are to humans or pets. The entire basis of the use of pesticides is differential sensitivity of species to chemicals. 

As a common example, think of the spray you use to kill ants, roaches, or other household insects. We spray this on ants and they die within seconds. However, if you spray the solution on your hand, you merely wash it off and don t typically notice any effect. This illustrates the extreme range of chemical sensitivity across species. 

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Based upon the available data, hamsters appear to be more resistant than other tested species to the lethal effects of acute exposure to monomethylhydrazine. Within similar exposure durations, the data expressed as concentration time (Ct) products suggest similar response sensitivity among squirrel monkeys, dogs, and mice. Based on 1-h LC50 values, the rhesus monkey and rats are somewhat more resistant to the lethal effects of monomethylhydrazine but not as resistant as hamsters. Squirrel monkeys and dogs, however, appear to be more sensitive than the rodents. These comparisons suggest species variability in the range of 2- to 3-fold. 

The 30-min and 1-, 4-, and 8-h AEGL-3 values were based on the highest concentration causing no mortality in the rat after a 30-min exposure (15 ppm) (Zwart et al. 1990). A UF of 3 was applied for interspecies extrapolation because little species variability is observed for lethal and nonlethal end points after exposure to phosgene. A UF of 3 was applied to account for sensitive human subpopulations due to the steep concentration-response curve and... 

Interspecies 3—little species variability is observed with both lethal and nonlethal end points in many studies after exposure to phosgene... 

Use of in vivo Tests. In vivo tests are more relevant indicators than are in vitro tests of immunotoxicity since the dynamic interactions between the various immuno-components, as well as the pertinent pharmacokinetic (absorption, distribution, plasma concentrations) and metabolic factors, are taken into consideration. However, it is important to select the appropriate animal model and to design the protocol such that it will accurately reflect drug (or relevant metabolite) exposure to humans. For example, one should consider species variability when selecting the animal model, since biological diversity may further obscure the ability to accurately predict human toxicity. 

Species variable mass mass molar cone./ molar mass mole mole/mass mass mass... 

Metabolic differences also account for the great species variability in methyl alcohol toxicity with humans and nonhuman primates being uniquely sensitive. (A relatively poor ability to metabolize the methanol-metabolized formate in these species leads to increased blood formate levels and subsequent metabolic acidosis and neuronal toxicity.)... 

The//(tissue) values are averaged for the species, this average is assumed to be the value for human, inserted back into the Oie-Tozer equation and combined with the measured value of /,(piasma) in human to obtain a predicted value for human VD. However, despite its increased complexity it does not offer additional accuracy over the above mentioned dog-human proportionality method and may only be most appropriate when plasma protein binding shows considerable inter-species variability. 

With the demonstration of species variability in response to the various oximes, it was noted that results obtained with a particular organophosphate were not obtained with other agents, even if... 

The next issue to discuss is the diversity of connexins, i.e. the various isoforms, and species variability. Gap junctional channels exist in a broad variety of tissues including the heart, vascular system, brain, epithelial tissues, uterus, lens cells, pancreas and kidney. However, these tissues are connected by different isoforms of gap junctional connexins which can be distinguished with regard to their molecular weight. These differences are mainly due to various lengths of the C-terminal loop. 

Regarding species variability there are some points to mention. First, a variability in the distribution pattern of a distinct connexin isoform is possible, for example with Cx40 which is normally found in atria of many species but not in rat atria. The details for these species differences with regard to the distribution of connexins in the heart are given in chapter 3. 

Fig. 13. Synopsis of the physiological regulators of gap junction channels. = PKC changes the substate of conductance, =not found by all investigators as differences between the various isoforms of connexins or species variabilities. 

Similarly, De Mello [1989] reported on an improvement in intercellular coupling by the P-adrenoceptor agonist isoproterenol in cardiac cell pairs. Thus, stimulation of P-adrenoceptors can be assumed to result in enhancement of intercellular coupling, at least in some preparations. However, on the basis of the hndings of Kwak and Jongsma [1996] on a lack of the effect of PKA to alter gap junction conductance in rat cardiomyocytes, caution seems necessary and species variability or tissue variability seems to play an important role. 

Because of the first of these uncertainties (the extrapolation across species), assessments of risks to human health apply an uncertainty or safety factor of 100 to the experimentally derived no observed adverse effect concentration (NOAEC), in other words the NOAEC is divided by 100 to derive a no-effect level for human toxicity. This factor has been used since 1961, when it was chosen on an essentially arbitrary basis (RCEP, 2003, p22). In the assessment of risks to the environment, application factors of 10, 50, 100 or 1000 are applied to the results of tests carried out on specific species,2 depending on the species used and whether the tests were long term or short term. Evidence to the Royal Commission on Environmental Pollution (RCEP) for their report Chemicals in products indicated that these are merely extrapolation factors — they express the statistical variability of test results but do not effectively take into account inter-species variability, the vulnerability of threatened species, lifetime exposures or the complexity of biological systems... 

Toxicity data are used to assess occupational exposure hazards associated with materials used in a process and are communicated through the use of Permissible or Occupational Exposure Limits (PEL or OEL). OELs are usually set based on a combination of the inherent toxicological hazard of a chemical and a series of safety factors such as intra-species variability in test results, the nature and severity of the effect, and the adequacy and quality of the information. OELs are set to protect workers under the general assumption that they are being exposed to any... 

Rodriguez-Arnaiz, R., Vogel, E.W. Szakmary, A. (1993) Strong intra-species variability in the metabolic conversion of six procarcinogens to somatic cell recombinagens in Drosophila. Mutagenesis, 8, 543-551... 

The density, temperature, and species variables follow exactly the earlier definitions throughout the chapter. 

In addressing consumer safety the VPC achieves this by consideration of the toxicological data and the no effect level (NEL = No observed Effect Level) for that substance in experimental animals. This, together with an additional safety factor to allow for any inter-species and intra-species variability, is used to calculate the acceptable daily intake (ADI). For an adult human the ADI is calculated from the NEL by using the following formula for a 60 kg person ... 

Details on many of the environmental factors which can cause concentration change are beyond the scope of this book. It is important to realize that such things as species variability, air temperature, humidity, irradiation, or trace materials in the air all can influence mi-... 

Acute oral toxicity values for lewisite have been summarized by Watson and Griffin (1992). The only available oral LD50 is that for the rat (50 mg/kg). Lethality values for other routes of exposure indicate some species variability but the values differ by less than an order of magnimde for any particular exposure route. 

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