Sex differences in the toxicokinetics of inhaled solvent vapors in humans 2. 2-propanol

The aim of this study was to evaluate possible sex differences in the inhalation toxicokinetics of 2-propanol vapor. Nine women and eight men were exposed on different occasions for 2 h during light physical exercise (50 W) to 2-propanol (350 mg/m3) and to clean air (control exposure). The level corresponds to the Swedish occupational exposure limit. 2-Propanol and its metabolite acetone were monitored up to 24 h after exposure in exhaled air, blood, saliva, and urine by headspace gas chromatography. Body fat and lean body mass were estimated from sex-specific equations using bioelectrical impedance, body weight, height, and age. Genotypes were determined by PCR-based assays for alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1). The CYP2E1 phenotype was assessed by the 2-h plasma 6-hydroxychlorzoxazone/chlorzoxazone metabolic ratio in vivo. The toxicokinetic profile in blood was analyzed using a one-compartment population model. The following sex differences were significant at the p = 0.05 level (Student's t test). The respiratory uptake was lower and the volume of distribution smaller in females. The women had a slightly shorter half-time of 2-propanol in blood and a higher apparent total clearance when corrected for body composition. However, women reached approximately four times higher 2-propanol levels in exhaled air at 10-min postexposure and onward. Acetone in blood was markedly higher in females than in males in the control experiment and slightly higher following exposure to 2-propanol. A marked sex difference was that of a 10-fold higher in vivo blood:breath ratio in men, suggesting sex differences in the lung metabolism of 2-propanol. The most marked sex difference was that of salivary acetone, for which an approximately 100-fold increase was seen in women, but no increase in men, after exposure to 2-propanol compared to clean air. The toxicokinetic analysis revealed no significant differences in toxicokinetics between subjects of different metabolic genotypes or phenotypes. In conclusion, the study indicates several sex differences in the inhalation toxicokinetics of 2-propanol. Most of these differences are consistent with anatomical differences between women and men. However, body build can not explain the sex differences in 2-propanol levels in expired air and acetone in saliva.     

Sex differences in urinary levels of several biological indicators of exposure: a human volunteer study

The aim of the study was to quantify the variability on biological indicators of exposure between men and women for three well known solvents: methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1-trichloroethane. Another purpose was to explore the effect of selected CYP2E1 polymorphisms on the toxicokinetic profile.Controlled human exposures were carried out in a 12 m³ exposure chamber for each solvent separately, during 6 h and at half of the threshold limit value. The human volunteers groups were composed of ten young men and fifteen young women, including ten women using hormonal contraceptive.An analysis of variance mainly showed an effect on the urinary levels of several biomarkers of exposure among women due to the use of hormonal contraceptive, with an increase of more than 50% in metabolites concentrations and a decrease of up to 50% in unchanged substances concentrations, suggesting an increase in their metabolism rate. The results also showed a difference due to the genotype CYP2E1*6, when exposed to methyl ethyl ketone, with a tendency to increase CYP2E1 activity when volunteers were carriers of the mutant allele.Our study suggests that not only physiological differences between men and women but also differences due to sex hormones levels can have an impact on urinary concentrations of several biomarkers of exposure. The observed variability due to sex among biological exposure indices can lead to misinterpretation of biomonitoring results. This aspect should have its place in the approaches for setting limits of occupational exposure.     

m-Xylene inhalation destroys cytochrome P-450 in rat lung at low exposure

Rats were exposed to 0, 75, 150 or 300 ppm (1 ppm=1 cm³/m³=4.35 mg/m³) m-xylene for 24 h and then killed. In the lungs, the cytochrome P-450 decreased to 45, 13 and 20% of the control value with the increasing exposure intensity and the activity of 7-ethoxycoumarin O-deethylase to 70, 27 and 14%, respectively. The activity of epoxide hydrolase increased slightly after exposures both at 150 (1.6-fold) and 300 cm³/m³ (1.4-fold), while the other measured drug-metabolizing enzyme activities showed no consistent changes. The non-protein sulfhydryl group content of the lungs was not affected. The concentrations of m-xylene in blood indicated that the solvent uptake increased in the different exposure groups more than expected, based on atmospheric concentrations alone. Morphologic studies of the lungs with scanning electron microscopy showed no apparent changes after exposure to 300 cm³/m³ or after a high oral dose (2 ml/kg/day, 3 days).Inhalation exposure to m-xylene for 5 weeks (7 h/day, 4 days/week) at a concentration of 300 ppm lowered the contents of cytochrome P-450 in rat lungs to 65% and the activity of 7-ethoxycoumarin O-deethylase to 41% without any other marked effects on the other drug-metabolizing enzymes or on the levels of non-protein sulfhydryl groups.In this study, the selective destruction of cytochrome P-450 in rat lung could be shown both after acute and subacute exposures and at concentrations low enough to warrant occupational concern.     

Formation, characterization, and fate of inhaled drug nanoparticles

Nanoparticles bring many benefits to pulmonary drug delivery applications, especially for systemic delivery and drugs with poor solubility. They have recently been explored in pressurized metered dose inhaler, nebulizer, and dry powder inhaler applications, mostly in polymeric forms. This article presents a review of processes that have been used to generate pure (non polymeric) drug nanoparticles, methods for characterizing the particles/formulations, their in-vitro and in-vivo performances, and the fate of inhaled nanoparticles.     

Single-dose toxicokinetics ofN-nitrosomethylethylamine andN-nitrosomethyl (2,2,2-trideuterioethyl)amine in the rat

To investigate the origins of an organotropic shift toward increasing esophageal carcinogenicity and DNA alkylation caused by -trideuteration of the hepatocarcinogen,N-nitrosomethylethylamine (NMEA), the single-dose toxicokinetics of NMEA andN-nitrosomethyl(2,2,2-trideuterioethyl)amine (NMEA-d ₃) has been characterized in 8-week-old male Fischer 344 rats by analysis using high performance liquid chromatography of serial blood samples. An i.v. bolus dose of 0.6 mol/kg to rats revealed biphasic first order elimination with a terminal half-life of 9.46 ± 0.69 min for unchanged NMEA and 28.9 ± 2.4 min for total radioactivity. Extensive conversion to polar metabolites was observed in the chromatograms. The systemic blood clearance and apparent steadystate volume of distribution for unchanged NMEA were 39.9 ± 4.6 ml/min/kg and 496 ± 36 ml/kg, respectively. There was negligible plasma protein binding and no detectable NMEA was excreted unchanged in the urine. Larger doses given by gavage indicated a systemic bioavailability of 25 ± 1%. Similar doses of NMEA-d ₃ given to other groups of rats revealed no significant differences in any of the toxicokinetic parameters. NoN-nitrosomethyl (2-hydroxyethyl)amine was found as a detectable metabolite of NMEA or NMEA-d ₃ in any of the blood or urine samples which were analyzed. When considered together, the data suggest that previously observed differences in organ specificity for the carcinogens, NMEA and NMEA-d ₃, are not due to differences in the total amounts of nitrosamine reaching particular tissues, but may have other localized causes such as differences in the enzymes responsible for metabolism which are present in each tissue. Such differences may make too small a contribution to the total systemic clearance to be detectable in that parameter, but at the level of the fraction of a dose that alkylates DNA they may be important.     

Tissue distribution and proinflammatory cytokine induction by the trichothecene deoxynivalenol in the mouse: comparison of nasal vs. oral exposure

Oral exposure to the trichothecene deoxynivalenol (DON), a common cereal grain contaminant, adversely affects growth and immune function in experimental animals. Besides foodborne exposure, the potential exists for DON to become airborne during the harvest and handling of grains and therefore pose a risk to agricultural workers. The purpose of this study was to compare the effects of oral and intranasal exposure to DON (5 mg/kg bw) on tissue distribution and proinflammatory cytokine induction in the adult female mouse. Competitive direct ELISA revealed that, regardless of exposure route, DON concentrations in plasma, spleen, liver, lung and kidney were maximal within 15–30 min and declined by 75–90% after 120 min. However, plasma and tissue DON concentrations were 1.5–3 times higher following intranasal exposure as compared to oral exposure. The functional significance of elevated DON tissue concentrations was assessed by measuring IL-1β, IL-6, and TNF- mRNA responses in spleen, liver and lung. Oral exposure to DON-induced robust proinflammatory cytokine gene expression after 60 and 120 min. In contrast, inductions of IL-1β, IL-6 and TNF- mRNAs in nasally exposed mice were 2–10, 2–5 and 2–4 times greater, respectively, than those in the tissues of orally exposed mice. Taken together, these data suggest that DON was more toxic to the mouse when nasally exposed than when orally exposed, and that this might relate to greater tissue burden of the toxin.     

Assimilation efficiency and toxicokinetics of 14C-lindane in the terrestrial isopod Porcellionides pruinosus: the role of isopods in degradation of persistent soil pollutants

An achievable way to evaluate the bioavailability of a certain toxic in the environment is to measure the concentration inside soil organisms. Non-target saprotrophic organisms like isopods are often exposed to agrochemicals or other kind of persistent chemicals. In this study the isopod Porcellionides pruinosus was exposed to a constant concentration of Lindane (-HCH) via food. Using toxicokinetic models the bioaccumulation and fate of the pesticide by isopods was assessed and compared with previous studies, where an unexpected decrease in -HCH concentration was observed. Animal body burdens showed higher values, and a lower assimilation rate constant, although the elimination rate constant was twice the value previously observed. It was also observed that a significant amount of -HCH had an unknown fate. To discover its possible destiny, a factorial experiment was carried out using two types of CO₂ traps and contaminated leaves in the presence and absence of isopods. It was concluded that isopod activity might have been responsible for a more rapid biotransformation of -HCH in leaves, since the amount of the pesticide is reduced in their presence.     

Enzyme induction by ethanol consumption affects the pharmacokinetics of inhaledm-xylene only at high levels of exposure

The experimental study with rats was undertaken to verify the working hypothesis that enzyme induction caused by ethanol consumption affects the kinetics ofm-xylene only at a high level of exposure.m-Xylene was administered to ethanol-treated rats either perorally (0.01, 0.02 or 0.1 ml/kg) or by inhalation (50, 100 or 500 ppm each for 6 h) and the concentration ofm-xylene in the blood and the urinary excretion of am-xylene metabolite (m-methyl hippuric acid orm-MHA) were measured with time. The ethanol consumption, which increased the in vitrom-xylene metabolism about 5-fold, had no effect on the metabolism of inhaledm-xylene in vivo until the exposure concentration was raised to 500 ppm. On the other hand, metabolism ofm-xylene after oral administration was markedly enhanced at any dose by the consumption, as evidenced by a decrease in the blood concentration ofm-xylene together with an increase in the urinary excretion ofm-MHA. These findings indicate that enzyme induction does not affect the pharmacokinetics of inhaledm-xylene when its exposure concentration is low. This may be because the hepatic blood flow, rather than the enzyme activity, rate-limits the metabolism ofm-xylene, which is highly metabolized in the liver.     

Effect of incomplete removal of the tert-butoxycarbonyl protecting group during synthesis of a pharmaceutical drug substance on the residual solvent analysis

During development of the residual solvent method using headspace-GC for a drug substance, an unexpected peak was observed in the chromatography. GC–MS analysis confirmed the unknown peak identity as isobutylene. An understanding of the source of the isobutylene was required in order to develop appropriate impurity and residual solvent control strategies for the drug substance. The experiments performed to determine the source of the isobutylene peak observed in the headspace-GC chromatography and how the tert-butoxycarbonyl (BOC) de-protection step used in the drug substance synthesis contributes to its observation are discussed.     

Bites by spiders of the family Theraphosidae in humans and canines.

Spiders of the family Theraphosidae occur throughout most tropical regions of the world. There have only been three case reports of bites by these spiders in Australia. The aim of this study was to describe the clinical effects of bites by Australian theraphosid spiders in both humans and canines. Cases of spider bite were collected by the authors over the period January 1978-April 2002, either prospectively in a large study of Australian spider bites, or retrospectively from cases reported to the authors. Subjects were included if they had a definite bite and had collected the spider. The spiders were identified by an expert arachnologist to genus and species level where possible. There were nine confirmed bites by spiders of the family Theraphosidae in humans and seven in canines. These included bites by two Selenocosmia spp. and by two Phlogiellus spp. The nine spider bites in humans did not cause major effects. Local pain was the commonest effect, with severe pain in four of seven cases where severity of pain was recorded. Puncture marks or bleeding were the next most common effect. In one case the spider had bitten through the patient's fingernail. Mild systemic effects occurred in one of nine cases. There were seven bites in dogs (Phlogellius spp. and Selenocosmia spp.), and in two of these the owner was bitten after the dog. In all seven cases the dog died, and as rapidly as 0.5-2h after the bite. This small series of bites by Australian theraphosid spiders gives an indication of the spectrum of toxicity of these spiders in humans. Bites by these spiders are unlikely to cause major problems in humans. The study also demonstrates that the venom is far more toxic to canines.     

Sex differences in tolerance to the locomotor depressant effects of lobeline in periadolescent rats

Lobeline is being tested in clinical trials as a pharmacotherapy for methamphetamine abuse and attention deficit hyperactivity disorder. Preclinical research demonstrates that lobeline produces locomotor hypoactivity apart from its therapeutic effects; however, the hypothesis that there are sex differences in hypoactivity or in the development of tolerance to its locomotor depressant effects has not been investigated. Periadolescent rats were injected with saline to determine baseline locomotor activity. Animals received saline or lobeline (1.0–10 mg/kg) daily for 7 consecutive days (post natal days 29–35), and were challenged with saline 24 h later to assess baseline activity. Lobeline produced hypoactivity in total horizontal activity and center distance travelled. Tolerance developed to the lobeline-induced hypoactivity and sex differences in lobeline tolerance were observed on both measures. Females acquired tolerance to lobeline 5.6 mg/kg at a slower rate than males. Saline challenge revealed a linear dose-dependent trend of hyperactivity on both measures, which indicates that rats exhibited altered locomotor behavior 24 h after the final lobeline treatment. These findings demonstrate sex differences in the hypoactive response to lobeline prior to puberty and suggest that females may experience more locomotor depressant effects than males. Chronic lobeline may induce hyperactivity following cessation of treatment.     

Sex differences in the medication choice for hypertension in general practice. A study with written case simulations

The objective of this study was to explore explanations for the preference of physicians to prescribe blockers to hypertensive men and diuretics to hypertensive women.A qualitative study among 12 family physicians was conducted with a combination of written case simulations, semistructured interviews and statements on attitudes of physicians towards antihypertensive drug choice.Among the male hypertensive cases the most frequently prescribed drugs were blockers, whereas among the female hypertensive cases diuretics were more often prescribed. Physician characteristics associated with a preferred prescribing of blockers to hypertensive men and diuretics to hypertensive women were: older age (no residency in family medicine), the believe that blockers are more effective in men with regard to lowering blood pressure and that diuretics are more effective in women, a nonevidence based attitude and a sexrelated attitude towards the choice of blockers and diuretics in general, and in particular towards the prescribing of blockers to hypertensive men because men have a higher absolute risk of coronary heart disease than women. An additional explanation for these findings may be the higher prevalence of ankle oedema among women. Patient characteristics associated with more prescribing of blockers to hypertensive men and diuretics to hypertensive women were: current employment and a "highrisk" profile in terms of blood pressure level and additional cardiovascular risk factors.Although, most considerations underlying a preferred prescribing of blockers to hypertensive men and diuretics to hypertensive women were not evidencebased, the actual choice of antihypertensive drug (diuretic or blocker) was evidencebased. These considerations may also play a role in the sex difference in the choice of calcium antagonists and angiotensin converting enzyme inhibitors and require further investigation.     

Sex differences in the reversal of fluoxetine-induced anorexia following raphe injections of 8-OH-DPAT

Rationale and objectives Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in the central nervous system and it is well established that this neurotransmitter plays an inhibitory role in the control of ingestive behavior. Administration of various 5-HT agonists and selective serotonin reuptake inhibitors, including fluoxetine (FLU), suppress food intake under free-feeding and food-restricted conditions. In contrast, activation of somatodendritc 5-HT_1A receptors in the raphe nuclei reduces forebrain 5-HT bioavailability and agonists of these receptors, including 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), reliably stimulate eating behavior.Methods In the present study male (n=8 per group) and female (n=8 per group) rats were pretreated with 8-OH-DPAT in an attempt to reverse FLUs inhibitory effect on feeding. 8-OH-DPAT was injected into either the dorsal or median raphe of male and female rats at doses of 0.1–0.4 nmol. FLU was then injected IP at a dose of 2 mg/kg. Both compounds were administered just prior to the onset of the dark cycle. Food intake was measured 2 h post-injection. Similar effects were also measured in female rats after ovariectomy.Results and conclusions FLU suppressed food intake comparably in male and female rats. Dorsal and median raphe injections of 8-OH-DPAT dose dependently reversed the anorectic effect of FLU in male rats. Higher doses of 8-OH-DPAT completely antagonized this response. In female rats, however, 8-OH-DPAT pretreatment was largely ineffective except in ovariectomized females where results were similar to male rats. These findings suggest that male and female rats are differentially sensitive to the ability of 5-HT_1A receptor agonists to antagonize the feeding suppressive action of FLU and imply a role for neuroendocrine mechanisms in enabling the somatodendritic autoreceptor to control serotonergic neurotransmission under these conditions.     

Genetic polymorphisms in hMTH1, hOGG1 and hMYH and risk of chronic benzene poisoning in a Chinese occupational population

Oxidative damage to DNA induced by benzene is an important mechanism of its genotoxicity, which leads to chronic benzene poisoning (CBP). Therefore, genetic variation in DNA repair genes may contribute to susceptibility to CBP in the exposed population. We hypothesized that single nucleotide polymorphisms (SNPs) in hMTH1, hOGG1 and hMYH genes are associated with risk of CBP. We genotyped SNPs at codon 83 of hMTH1, codon 326 of hOGG1, and codon 324 of hMYH in 152 CBP patients and 152 healthy workers occupationally exposed to benzene without poisoning manifestations. The genotypes were determined by polymerase chain reaction-restrained fragment length polymorphism (PCR-RFLP) technique. There were 2.51-fold [adjusted odds ratio (OR_adj), 2.51; 95% CI, 1.14-5.49; P = 0.02] and 2.49-fold (OR_adj, 2.49; 95% CI: 1.52-4.07; P < 0.01) increased risk of CBP for individuals carrying genotypes of hMTH1 83Val/Met + Met/Met and hOGG1 326Cys/Cys, respectively. Compared with individuals carrying genotypes of hOGG1 326Cys/Cys and hMYH 324His/His at the same time, there was a 0.33-fold (OR_adj, 0.33; 95% CI: 0.15-0.72; P < 0.05) decreased risk of CBP for those with genotypes of hOGG1 326Ser/Cys + Ser/Ser and hMYH 324His/Gln + Gln/Gln. In the smoking group, there was a 0.15-fold (OR_adj, 0.15; 95% CI, 0.03-0.68; P = 0.01) decreased risk of CBP for subjects carrying genotypes of hMYH 324His/Gln + Gln/Gln compared with those of genotype of hMYH 324His/His. Therefore, our results suggested that polymorphisms at codons 83 of hMTH1 and codon 326 of hOGG1 might contribute to CBP in a Chinese occupational population.     

Associations of ABCB1, NFKB1, CYP3A,and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients

Aim:

Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation.

Methods:

A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4^*1G, CYP3A5^*3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 −94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation.

Results:

The dose-adjusted trough concentration (C₀) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90.4±24.5 vs 67.8±26.8 (ng/mL)/(mg/kg), P=0.001]. ABCB1 3435 TT carriers had a significantly higher dose-adjusted C₀ of cyclosporine than CC carriers together with CT carriers [92.0±24.0 vs 68.4±26.5 (ng/mL)/(mg/kg), P=0.002]. Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C₀/D than carriers of other genotypes [97.2±21.8 vs 68.7±26.9 (ng/mL)/(mg/kg), P=0.001]. Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1 −94 ATTG ins/ins genotype had a significantly higher dose-adjusted C₀ than those with the −94 ATTG del/del genotype [75.9±32.9 vs 55.1±15.1 (ng/mL)/(mg/kg), P=0.026].

Conclusion:

These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine.     

Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats

Rationale Sex differences have been reported for the impact of nicotine and nonpharmacological cues on smoking. While nonpharmacological environmental stimuli have also been shown to influence nicotine self-administration in rats, there have been no attempts to examine the impact of sex differences in the contributions of nicotine and nondrug stimuli to this behavior.Objectives This experiment investigated sex differences in operant responding for nicotine in rats when drug infusions were delivered either in the absence of, or in combination with, a nonpharmacological stimulus.Methods Initially, male and female rats acquired self-administration for nicotine alone across a range of doses (0.03, 0.06, and 0.15 mg kg^–1 inf^–1, freebase). After stable acquisition, nicotine infusions were combined with a weakly reinforcing, compound visual stimulus.Results While there was no overall effect of dose on active lever responding for nicotine in the absence of the visual stimulus, female rats responded more on the reinforced lever than males at 0.06 and 0.15 mg kg^–1 inf^–1 on an FR5 schedule. However, they also showed increased responding on the nonreinforced lever compared to males at the same doses. Combining nicotine infusions with the visual stimulus doubled responding compared to nicotine alone at 0.03 and 0.06, but not at 0.15 mg kg^–1 inf^–1: this effect was significantly greater for female rats.Conclusions These data highlight the prominent contribution of nonpharmacological stimuli to nicotine-reinforced behavior across a range of doses in both male and female rats. They also reveal sex differences in operant responding for nicotine under conditions where a nonpharmacological stimulus is either absent, or combined with drug delivery.     

Sex differences in the burying behavior test in middle-aged rats: effects of diazepam

The full behavioral profile displayed during the burying behavior test was studied in middle aged (11-14 months) males, females with irregular estrous cycles, and females in persistent diestrus, with and without diazepam (0.5-2.0 mg/kg). Ambulation and motor coordination were also tested to discern behavioral changes from general motor alterations. Without diazepam treatment, middle-aged males showed longer burying behavior latencies, more prod explorations and less freezing than both groups of females. Untreated middle aged males also showed less cumulative burying and more immobility compared to females with irregular cycles. None of the parameters showed any difference between the female groups. Diazepam (0.5 and 1.0 mg/kg) increased burying behavior latency in females, but had no effect on any parameter in middle aged males. However, a higher dose (2.0 mg/kg) of diazepam increased immobility, freezing and the number of prod shocks and decreased prod explorations and groomings, but impaired motor coordination in males. In contrast with young males and females, diazepam at any dose reduced cumulative burying. Data are discussed on the bases of (1) sex and age differences in burying behavior and on (2) the anxiolytic-like action of diazepam and its side effects.     

Morphological characterization of the venom secretory epidermal cells in the stinger of marine and freshwater stingrays.

Marine and freshwater stingrays are characterized by the presence of one to three mineralized serrated stingers on the tail, which are covered by epidermal cells secreting venom. When these animals are dorsally touched, the stinger can be introduced into the aggressor by a whip reflex mechanism of the tail, causing severe mechanical injuries and inoculating the venom. Accidents in humans are frequent causing intense local pain, oedema and erythema. Bacterial secondary infection is also common. In addition, injuries involving freshwater stingrays frequently cause a persistent cutaneous necrosis. The exact localization of the venom secretory epidermal cells in the stinger is controversial, but it is known that it is preferentially located in the ventrolateral grooves. A comparative morphological analysis of the stinger epidermal tissue of different marine and freshwater Brazilian stingray species was carried out. The results indicate that in freshwater species there is a larger number of protein secretory cells, of two different types, spread over the whole stinger epidermis, while in marine species the protein secretory cells are located only around or inside the stinger ventrolateral grooves. These differences between the stingers of the two groups can justify the more severe envenomation accidents with the freshwater species when compared with the marine species.     

The use of Cav rather than AUC in safety assessment

Toxicokinetic data have traditionally been presented as maximum observed plasma concentrations (C_max) and area under the concentration time curve (AUC) values. These values have been used to compare exposures across studies and species to provide valuable interpretation of drug safety data. Increasingly, questions are asked of toxicology studies to more accurately describe the concentration effect relationships in terms of compound affinity for target and off-target receptors. C_max values can immediately be referenced to known pharmacological activities, particularly when the extent of plasma protein binding is taken into account. This provides a measure of the more pharmacologically relevant free drug exposure. AUC values on the other hand contain the component of time, which means that direct comparison to pharmacological activity values are not immediately possible. Conversion of AUC to average plasma concentration (C_av) provides a simple and convenient means to allow such a comparison without losing any information imparted by AUC values. In this paper, the benefit and advantage of applying C_av values is illustrated using examples taken from the literature.