Toxic-induced hypothermia and hypometabolism: Do they increase uncertainty in the extrapolation of toxicological data from experimental animals to humans?

doi:10.1016/S0149-7634(05)80098-3

Neuroscience & Biobehavioral Reviews

Volume 15, Issue 1, Spring 1991, Pages 95-98

https://doi.org/10.1016/S0149-7634(05)80098-3 Get rights and content

Commonly used experimental mammals, such as the rat and mouse, exhibit hypothermia and hypometabolism when exposed acutely to many drugs and other chemical substances. This toxic-induced hypothermic/hypometabolic state may be an inherently protective response that can reduce the lethality of a toxic insult. However, as body mass increases, the ability to lower body temperature in response to toxic insult is diminished. Hence, the presence of a protective hypothermic/hypometabolic response in small laboratory mammals and apparent lack thereof in larger species, such as humans, may represent an additional physiological dissimilarity which may underestimate the risk assessment of acute toxicological data. It is proposed that acute toxicological studies in rodents be performed at relatively warm ambient temperatures (ca. 28 to 32°C) to prevent toxic-induced hypothermia. This would assure a more uniform internal thermal environment between species, thus reducing a major physiological variable in species-to-species extrapolation.

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Cited by (28)

Concentration × time analyses of sensory irritants revisited: Weight of evidence or the toxic load approach. That is the question
2019, Toxicology Letters
Citation Excerpt :
Prevailing evidence suggests that the reflex-induced rodent-specific adaption to inhaled irritants cause bradypnea and associated hypothermia. In the wake of hypothermia, numerous physiological factors must be re-adjusted by the animal to maintain homeostasis (Gordon et al., 2008; Gordon, 1991, Gordon, 1993, Gordon, 2005). One developmental hallmark of this adaptation is the physiology-driven decreased maternal-placental-fetal transfer of oxygen, which can result in significant developmental delays (for details see Pauluhn, 2018).
The toxic effects resulting from inhalation exposure depend on both the concentration (C) of the inhaled substance and the exposure duration (t), including the assumptions that the exposure-limiting toxic effect is linearly linked with the accumulated C × t (inhaled dose), and detoxification or compensatory responses diminishing this dose are negligible. This interrelationship applies for both constant and fluctuating concentrations and is usually expressed by the toxic load equation Cⁿ × t = constant effect (k). The toxic load exponent ‘n’ is derived from both C- and t-dependent exponents with C^b2×t^b3 = k with n = b₂/b₃. This model is taken as a fundamental basis for assessing the acute hazard posed by atmospheric releases of noxious substances, whether deliberate or accidental. Despite its universal use, especially for inhaled irritants, the toxicological significance of this mathematical construct is still discussed controversially. With n = 1 this equation is called Haber’s rule. The underlying assumption is that the exposure-based calculated and the actually inhaled C^b2×t^b3 are identical. Unlike the calculated dose, the latter is dependent on the test species and its t-dependent change in respiratory minute volume (MV). The retention patterns of inhaled irritant vapors may differ in obligate nasal breathing rodents and oronasally breathing humans as well. Thus, due to the interdependence of n on both C, t and k, this mathematical construct generates a bioassay-specific ‘n’ which can hardly be considered as human-equivalent, especially following exposure to sensory irritants known to elicit reflex-related changes in MV. The C- and t-dependent impact on Cⁿ × t = k was analyzed with the sensory irritant n-butyl monoisocyanate and compared with t-dependent changes elicited by highly, moderately, and poorly water-soluble sensory irritants ammonia, toluene diisocyanate, and phosgene, respectively. This comparison reveals that n depends on several factors: In cases where MV is instantly and plateau-like depressed with onset of exposure, n appears to be most dependent on C^b2 × MV whereas for a similar slower time-dependent response n becomes more dependent on MV × t^b3. For any ensuing risk characterization that focuses on acute non-lethal threshold C^b2 × t^b3’s, the sensory irritation-related depression in MV must be known to arrive at meaningful conclusions. In summary, both Cⁿ- and t-dependent dosimetry-related pitfalls may occur in acute bioassays on rodents following inhalation exposure to irritants. These must be identified and dealt with judiciously prior to translation to apparently similar human exposures. By default, extrapolations from one duration to another should start with that Cⁿ × t eliciting the least depression in MV with n = 1.
Intranasal administration of sodium dimethyldithiocarbamate induces motor deficits and dopaminergic dysfunction in mice
2018, NeuroToxicology
Citation Excerpt :
NaDMDC elicited a hypothermia reaction 1 h after the i.n. administration, which was reversible, disappearing within the second hour. The onset of hypothermia after the acute administration of toxins is a phenomena well described for different substances, including metals (zinc, cadmium and lead), organic solvents (short chain alcohols, sulfonate), and pesticides (Gordon, 1991). Our research group has recently observed that i.n. MPTP administration causes a significant hypothermia that begins 1 h and remains for 6 h after its administration (unpublished data).
The primary etiology of Parkinson’s disease (PD) remains unclear, but likely reflects a combination of genetic and environmental factors. Exposure to some pesticides, including ziram (zinc dimethyldithiocarbamate), is a relevant risk factor for PD. Like some other environmental neurotoxicants, we hypothesized that ziram can enter the central nervous system from the nasal mucosa via the olfactory nerves. To address this issue, we evaluated the effects of 1, 2 or 4 days of intranasal (i.n., 1 mg/nostril/day) infusions of sodium dimethyldithiocarbamate (NaDMDC), a dimethyldithiocarbamate more soluble than ziram, on locomotor activity in the open field, neurological severity score and rotarod performance. We also addressed the effects of four daily i.n. NaDMDC infusions on olfactory bulb (OB) and striatal measures of cell death, reactive oxygen species (ROS), tyrosine hydroxylase, and the levels of dopamine, noradrenaline, serotonin, and their metabolites. A single i.n. administration of NaDMDC did not significantly alter the behavioral measures. Two consecutive days of i.n. NaDMDC administrations led to a transient neurological deficit that spontaneously resolved within a week. However, the i.n. infusions of NaDMDC for 4 consecutive days induced motor and neurological deficits for up to 7 days after the last NaDMDC administration and increased striatal TH immunocontent and dopamine degradation within a day of the last infusion. Pharmacological treatment with the anti-parkinsonian drugs l-DOPA and apomorphine improved the NaDMDC-induced locomotor deficits. NaDMDC increased serotonin levels and noradrenaline metabolism in the OB 24 h after the last NaDMDC infusion, ROS levels in the OB 2 h after the last infusion, and striatum 2 and 24 h after the last infusion. These results demonstrate, for the first time, that i.n. NaDMDC administration induces neurobehavioral and neurochemical impairments in mice. This accords with evidence that dimethyldithio-carbamate exposure increases the risk of PD and highlights the possibility that olfactory system could be a major route for NaDMDC entry to central nervous system.
Upper respiratory tract nociceptor stimulation and stress response following acute and repeated Cyfluthrin inhalation in normal and pregnant rats: Physiological rat-specific adaptions can easily be misunderstood as adversities
2018, Toxicology Letters
Citation Excerpt :
For all tests the criterion for statistical significance is set at P ≤ 0.05. The typical series of rodent (rat)-specific evidence of upper respiratory tract sensory irritation was shown to be associated with decreased ventilation, bradycardia and decreased cardiac output, hypothermia and reduced metabolism as well as changes in acid-base status, when analyzed (Alarie, 1966, 1973, 1981; Gordon, 1991, 1993, 2005; Mautz and Bufalino, 1989; Pauluhn and Machemer, 1998; Pauluhn and Mohr, 2000; Watkinson and Gordon, 1993). These interrelated events occurred both for chemically reactive respiratory tract cytotoxic and sensory irritants that do not gain access to the CNS (Gordon et al., 2007; Li et al., 2013; Luo et al., 2014) and for non-respiratory tract neuroexcitatory irritants such as Cyfluthrin (Pauluhn, 1998, 1999; Pauluhn and Machemer, 1998).
This paper reviews the results from past regulatory and mechanistic inhalation studies in rats with the type II pyrethroid Cyfluthrin. Apart from many chemical irritants, Cyfluthrin was shown to be a neuroexcitatory agent without any inherent tissue-destructive or irritant property. Thus, any Cyfluthrin-induced neuroexcitatory afferent sensory stimulus from peripheral nociceptors in the upper respiratory tract is likely to be perceived as a transient stimulus triggering annoyance and/or avoidance by both rats and humans. However, while thermolabile rats respond to such stresses reflexively, homeothermic humans appear to respond psychologically. With this focus in mind, past inhalation studies in rats and human volunteers were reevaluated and assessed to identify common denominators to such neuroexcitatory stimuli upon inhalation exposure. This analysis supports the conclusion that the adaptive physiological response occurring in rats secondary to such chemosensory stimuli requires inhalation exposures above the chemosensory threshold. Rats, a species known to undergo adaptively a hibernation-like physiological state upon environmental stresses, experienced reflexively-induced bradypnea, bradycardia, hypothermia, and changes in acid-base status during inhalation exposure. After cessation of the sensory stimulus, rapid recovery occurred. Physiological data of male and female rats from a 4-week repeated inhalation study (exposure 6-h/day, 5-times/week) were used to select concentration for a 10-day developmental inhalation toxicity study in pregnant rats. Maternal hypothermia and hypoventilation were identified as likely cause of fetal and placental growth retardations because of a maternal adaptation-driven reduced feto-placental transfer of oxygen. In summary, maternal reflex-hypothermia, reduced cardiac output and placental perfusion, and disruption of the gestation-related hyperventilation are believed to be the maternally mediated causes for developmental impairments. Thus, inhaled chemosensory substances may appear to be more toxic in rats than they will be in humans because the thermoregulatory response of rats to such stimuli can cause profound physiological adaptions that can easily be misunderstood as adversities in conventional inhalation studies in small rodents. The afferent threshold triggering such outcomes in rodents translate to perceptions of annoyance in humans. Consequently, hazard characterization and human risk assessment need to be focused on the chemosensory threshold rather than endpoints occurring downstream to rodent-specific homeostasis.
Thermoregulatory responses to environmental toxicants: The interaction of thermal stress and toxicant exposure
2008, Toxicology and Applied Pharmacology
Thermal stress can have a profound impact on the physiological responses that are elicited following environmental toxicant exposure. The efficacy by which toxicants enter the body is directly influenced by thermoregulatory effector responses that are evoked in response to high ambient temperatures. In mammals, the thermoregulatory response to heat stress consists of an increase in skin blood flow and moistening of the skin surface to dissipate core heat to the environment. These physiological responses may exacerbate chemical toxicity due to increased permeability of the skin, which facilitates the cutaneous absorption of many environmental toxicants. The core temperature responses that are elicited in response to high ambient temperatures, toxicant exposure or both can also have a profound impact on the ability of an organism to survive the insult. In small rodents, the thermoregulatory response to thermal stress and many environmental toxicants (such as organophosphate compounds) is often biphasic in nature, consisting initially of a regulated reduction in core temperature (i.e., hypothermia) followed by fever. Hypothermia is an important thermoregulatory survival strategy that is used by small rodents to diminish the effect of severe environmental insults on tissue homeostasis. The protective effect of hypothermia is realized by its effects on chemical toxicity as molecular and cellular processes, such as lipid peroxidation and the formation of reactive oxygen species, are minimized at reduced core temperatures. The beneficial effects of fever are unknown under these conditions. Perspective is provided on the applicability of data obtained in rodent models to the human condition.
Thermoregulation and its influence on toxicity assessment
2008, Toxicology
Citation Excerpt :
Assessing the risk of chemicals and drug safety relies on data collected from laboratory rodents. The exaggerated hypothermic response of rodents to a toxic insult may in fact lead the risk assessor to underestimate the toxicity of drugs and chemicals when extrapolating to humans (Gordon, 1991, 1996; Watkinson and Gordon, 1993). In other words, a moderate amount of hypothermia is protective to many types of toxic insults and the hypothermic response is attenuated with increasing body mass.
The thermoregulatory system of laboratory rodents is susceptible to a variety of chemical toxicants. Because temperature directly affects the reaction of virtually all biological processes, it is critical to consider how changes in the thermoregulatory response to a toxicant may affect physiological, behavioral, and pathological endpoints. Researchers in industry and government laboratories are often faced with addressing how changes in body temperature of their experimental subjects may affect the outcome of a particular toxicity test and/or screening panel. However, many toxicologists are either unaware of the importance or ignore the potential impact of a toxic-induced change in body temperature. This paper endeavors to summarize the importance of thermoregulation in the study of toxicology and propose recommendations for thermometry that researchers may utilize in their toxicological studies.
Comparison of deramciclane to benzodiazepine agonists in behavioural activity of mice and in alcohol drinking of alcohol-preferring rats
2004, Pharmacology Biochemistry and Behavior
Interactions between alcohol and traditional benzodiazepine anxiolytics hamper the treatment of alcoholism-related anxiety disorders. Serotonin 5-HT₂ receptor antagonists, such as deramciclane, are anxiolytic, and considering their pharmacological profile, they might benefit alcoholics with comorbid anxiety. We studied the effects of acute deramciclane (1, 3 and 10 mg/kg ip) on alcohol drinking of alcohol-preferring AA rats drinking 10% (vol/vol) ethanol solution in a 4-h limited-access paradigm. Thereafter, a 5-day repeated-treatment experiment was carried out, under corresponding test design, with deramciclane (3 mg/kg ip) as a test drug and midazolam (1 mg/kg ip) as a benzodiazepine reference compound. Deramciclane had no effect on alcohol consumption in either acute or repeated dosing study. Midazolam increased ethanol drinking, as expected, when administered on successive days. A modified functional observational battery (FOB) procedure was applied to study neurological, behavioural and autonomic effects induced by deramciclane (1–30 mg/kg po) and diazepam (1–30 mg/kg po) in mice at 30 min, 2 h and 4 h after dosing. Deramciclane had a mild dopamine D₂ receptor antagonism-like effect at the highest dose. The effects of diazepam were predictable, myorelaxation-induced motor impairment and anxiolysis-related hyperlocomotion in a novel environment being the characteristic features at the two highest doses. Deramciclane appears to be a safe and well-tolerated drug and we suggest that it might be useful in the treatment of anxiety in alcoholics.

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¹: This paper has been reviewed by the Health Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

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Technical Session: Basic Mechanisms Involved In Toxic EffectsToxic-induced hypothermia and hypometabolism: Do they increase uncertainty in the extrapolation of toxicological data from experimental animals to humans?1

Neurosci. Biobehav. Rev.

Essays Toxicol.

Toxicol. Appl. Pharmacol.

Environ. Res.

Alcohol

Toxicology

Neurotoxicol. Teratol.

Fundam. Appl. Toxicol.

Toxicology

J. Pharm. Sci.

Toxicol. Appl. Pharmacol.

Acute toxicity in theory and practice

Scaling of physiological processes in homeothermic animals

Annu. Rev. Physiol.

Hypothermia in organophosphate poisoning and response to PAM

J. S. C. Med. Assoc.

Technical Session: Basic Mechanisms Involved In Toxic Effects
Toxic-induced hypothermia and hypometabolism: Do they increase uncertainty in the extrapolation of toxicological data from experimental animals to humans?1