Persistent Toxic Effects Research Articles

Extended Follow-Up of Chronic Immune-Related Adverse Events Following Adjuvant Anti–PD-1 Therapy for High-Risk Resected Melanoma

Anti-programmable cell death-1 (anti-PD-1) improves relapse-free survival when used as adjuvant therapy for high-risk resected melanoma. However, it can lead to immune-related adverse events (irAEs), which become chronic in approximately 40% of patients with high-risk melanoma treated with adjuvant anti-PD-1. To determine the incidence, characteristics, and long-term outcomes of chronic irAEs from adjuvant anti-PD-1 therapy. This retrospective multicenter cohort study analyzed patients treated with adjuvant anti-PD-1 therapy for advanced and metastatic melanoma between 2015 and 2022 from 6 institutions in the US and Australia with at least 18 months of evaluable follow-up after treatment cessation (range, 18.2 to 70.4 months). Incidence, spectrum, and ultimate resolution vs persistence of chronic irAEs (defined as those persisting at least 3 months after therapy cessation). Descriptive statistics were used to analyze categorical and continuous variables. Kaplan-Meier curves assessed survival, and Wilson score intervals were used to calculate CIs for proportions. Among 318 patients, 190 (59.7%) were male (median [IQR] age, 61 [52.3-72.0] years), 270 (84.9%) had a cutaneous primary, and 237 (74.5%) were stage IIIB or IIIC at presentation. Additionally, 226 patients (63.7%) developed acute irAEs arising during treatment, including 44 (13.8%) with grade 3 to 5 irAEs. Chronic irAEs, persisting at least 3 months after therapy cessation, developed in 147 patients (46.2%; 95% CI, 0.41-0.52), of which 74 (50.3%) were grade 2 or more, 6 (4.1%) were grade 3 to 5, and 100 (68.0%) were symptomatic. With long-term follow-up (median [IQR], 1057 [915-1321] days), 54 patients (36.7%) experienced resolution of chronic irAEs (median [IQR] time to resolution of 19.7 [14.4-31.5] months from anti-PD-1 start and 11.2 [8.1-20.7] months from anti-PD-1 cessation). Among patients with persistent irAEs present at last follow-up (93 [29.2%] of original cohort; 95% CI, 0.25-0.34); 55 (59.1%) were grade 2 or more; 41 (44.1%) were symptomatic; 24 (25.8%) were using therapeutic systemic steroids (16 [67%] of whom were on replacement steroids for hypophysitis (8 [50.0%]) and adrenal insufficiency (8 [50.0%]), and 42 (45.2%) were using other management. Among the 54 patients, the most common persistent chronic irAEs were hypothyroid (38 [70.4%]), arthritis (18 [33.3%]), dermatitis (9 [16.7%]), and adrenal insufficiency (8 [14.8%]). Furthermore, 54 [17.0%] patients experienced persistent endocrinopathies, 48 (15.1%) experienced nonendocrinopathies, and 9 (2.8%) experienced both. Of 37 patients with chronic irAEs who received additional immunotherapy, 25 (67.6%) experienced no effect on chronic irAEs whereas 12 (32.4%) experienced a flare in their chronic toxicity. Twenty patients (54.1%) experienced a distinct irAE. In this cohort study of 318 patients who received adjuvant anti-PD-1, chronic irAEs were common, affected diverse organ systems, and often persisted with long-term follow-up requiring steroids and additional management. These findings highlight the likelihood of persistent toxic effects when considering adjuvant therapies and need for long-term monitoring and management.

Toxic and Teratogenic Effects of Prenatal Alcohol Exposure on Fetal Development, Adolescence, and Adulthood.

Prenatal alcohol exposure (PAE) can have immediate and long-lasting toxic and teratogenic effects on an individual’s development and health. As a toxicant, alcohol can lead to a variety of physical and neurological anomalies in the fetus that can lead to behavioral and other impairments which may last a lifetime. Recent studies have focused on identifying mechanisms that mediate the immediate teratogenic effects of alcohol on fetal development and mechanisms that facilitate the persistent toxic effects of alcohol on health and predisposition to disease later in life. This review focuses on the contribution of epigenetic modifications and intercellular transporters like extracellular vesicles to the toxicity of PAE and to immediate and long-term consequences on an individual’s health and risk of disease.

Improving the safety of T-Cell therapies using an inducible caspase-9 gene.

Adoptive transfer of T cells can be an effective anticancer treatment. However, uncontrolled or unpredictable immediate or persistent toxic effects are a source of concern. The ability to conditionally eliminate aberrant cells invivo is therefore becoming a critical step for the successful translation of this approach to the clinic. We review the evolution of safety systems, focusing on a suicide switch that can be expressed stably and efficiently in human Tcells without impairing phenotype, function, or antigen specificity. This system is based on the fusion of human caspase-9 to a modified human FK-binding protein, allowing conditional dimerization in the presence of an otherwise bio-inert small molecule drug. When exposed to the synthetic dimerizing drug, the inducible caspase-9 becomes activated, resulting in the rapid apoptosis of cells expressing this construct. We have illustrated the clinical feasibility and efficacy of this approach after haploidentical hematopoietic stem cell transplant. Here we review the benefits and limitations of the approach.

The repellent and persistent toxic effects of essential oils against the poultry red mite, Dermanyssus gallinae

The economic impact of the poultry red mite, Dermanyssus gallinae, the lack of new acaricides, the occurrence of resistance and tighter legislation have all led to the need to find new ways to control this pest. One promising alternative method of control focuses on employing repellent and/or toxic effects of selected plant essential oils against D. gallinae. Ten essential oils (basil, thyme, coriander, eucalyptus, lavender, lemon, fir tree, oregano, mint, and juniper) were tested for the persistence of toxic and repellent effects. In filter-paper toxicity bioassays against D. gallinae, the best results were observed for lavender (more than 97% mortality after 48 and 72h) and thyme (84% at 72h) at a dose of 0.12mg/cm2. In addition, two oils showed significant persistent toxic effects 15 and 30 days post application to filter papers. Thyme was the most effective (100% mortality at 72h), followed by lavender (nearly 80% mortality after 72h). Out of the ten oils tested for their repellent effect, thyme was the strongest, with nearly 80% of the tested area avoided by mites; oregano caused a 60% avoidance and lavender exhibited an effect close to 40%. All other oils exhibited a repellent effect of less than 30%. None of the experiments showed a repellent effect for HM (commercial alimentary oil) or negative controls. We found that the thyme and lavender essential oils exhibited promising results when tested in vitro for toxic and repellent effects against D. gallinae; thus, we suggest that future experiments focus on in vivo tests using these oils in farm units.

Sorption and desorption of organophosphate pesticides, parathion and cadusafos, on tropical agricultural soils

Ecotoxicological impacts of organic pesticides on soil and aquatic ecosystems depend primarily on their behavior in soils. Actual pesticide knowledge is mostly restricted to soils from temperate climates, whereas knowledge of pesticide behavior in tropical soils is scarce. Here, the sorption behavior of two organophosphorous insecticides, parathion and cadusafos, was studied in three agricultural soil samples from central Mexico, Vertisols and Andosols. Using 14C-labeled substances, we assessed sorption and desorption properties in classical batch equilibrium and static soil incubation experiments. Our results show that cadusafos was less sorbed by the various soils (K d values 7.6–12.7 L kg−1) compared with parathion (K d values 38.6–74.9 L kg−1), despite similar log K ow values. Cadusafos exhibited a greater reversibility of sorption than parathion in both soil types. Time-dependent sorption was quantitatively significant, leading to a rapid decrease in the concentration of available insecticide. This finding is partly due to the formation of non-extractable, bound residues. The decrease in the available concentration of both insecticides was greater in the Andosol compared with the Vertisols. Soil organic matter clearly influenced the sorption behavior and availability of parathion. On the other hand, the sorption of cadusafos was more influenced by other soil properties such as clay content and cation exchange capacity. Calculation of residual insecticide levels in the soil solution suggests that both insecticides may have persistent toxic effects in the studied soils.

ULTRAVIOLET FLUORESCENCE SPECTROSCOPY (UVFS): A NEW MEANS OF DETERMINING THE EFFECT OF CHEMICAL DISPERSANTS ON OIL SPILLS

ABSTRACT Crude oils dispersed in seawater produce distinct emission spectra when exposed to ultraviolet (UV) light. The spectra can be used to estimate how effectively oil is dispersed by chemical methods. Oil dispersants (such as Corexit 9500) have a pronounced effect on water-based UV spectra, strongly enhancing emission at 445 nm. This enhancement of fluorescence over the 455 nm bandwidth is the result of dispersant breaking up higher molecular weight (>3 ring) polycyclic aromatic hydrocarbons (PAHs) into stable suspensions of small droplets. Ultraviolet fluorescence spectroscopy (UVFS) has been tested as a rapid analytical tool in the laboratory and in a wave tank designed to investigate the response of crude oils to dispersants and a range of energy dissipation rates. The results obtained with UVFS are consistent with standard chemical analyses, confirming that the method can be employed as a rapid, quantitative measure of dispersed oil concentration. Given that higher molecular weight PAHs are associated with many of the persistent toxic effects of crude oils on marine organisms, UVFS may also prove to be a useful tool for tracking these fractions during dispersed oil toxicity assays.

Nerve conduction, visual evoked responses and electroretinography in tunnel workers previously exposed to acrylamide and N-methylolacrylamide containing grouting agents

The study examines possible persisting effects on the peripheral nervous system and visual system in tunnel workers previously exposed to acrylamide and N-methylolacrylamide during grouting work. We compared neurophysiological function in 44 tunnel workers previously exposed during grouting operations (2–10 years post exposure), with 49 tunnel workers with no history of exposure to acrylamide. Nerve conduction velocities (NCV), distal delay, F-response and amplitude in median and ulnar nerves of the right arm, peroneal, sural and tibial nerves of the right leg, visual evoked response (VER) and electroretinography (ERG) were measured. VER and ERG were also performed in 24 subjects more recently exposed to acrylamide grout (16 months post exposure). Exposure to acrylamide containing grouts was assessed by questionnaires. A statistically significant reduction in the mean sensory NCV of the sural nerve (p=0.005), as well as a non-significant reduction of sural amplitude was found in the previously exposed group compared to the control group. VER latencies to the onset of the occipital potential (N75) were prolonged in both exposed groups compared to the control group (p<0.05). ERG 30 Hz flicker amplitude was reduced in the recently exposed group compared to the referents (p<0.05). The results indicate slight subclinical, but persistent toxic effects in the sural nerve and the visual system in tunnel workers exposed to N-methylolacrylamide and acrylamide during grouting operations.

Fourth International Conference on the Molecular Biology and Pathogenesis of the Clostridia. Abstracts of poster presentations.

Micro-organisms are vital for soil fertility and for the degradation of organic matter and pollutants in soils and sediments. Due to their function and ubiquitous presence micro-organisms can act as an environmentally very relevant indicator of pollution. Microbial tests should be used discriminatory for the establishment of soil and sediment quality guidelines. This review gives an evaluation of microbial toxicity tests and a novel method to derive quality guidelines.Long term microbial tests are generally less sensitive than short term tests. The toxic effects can be obscured by the activity of a few resistant micro-organisms, when for example soil respiration is used as a sum parameter during a long incubation period. Mineralization tests with high substrate concentrations which enable growth, are less sensitive than similar tests with low concentrations of substrate. The latter tests are more relevant for natural ecosystems.The often applied microbial toxicity tests can be categorized as single species tests, biomass measurements, carbon and nitrogen transformations, enzymatic tests and tests measuring changes in microbial diversity. Comparisons between tests can only be indicative because the relative sensitivity depends on the toxicants and soils used. The respiration rate per unit of biomass is a more sensitive indicator of toxic effects than the respiration rate or the amount of biomass alone. The autotrophic nitrification and acetylene reduction tests can be sensitive when short incubation times are used. The nitrogen mineralization, denitrification and many enzymatic tests are often not very sensitive. The urease activity is a relatively sensitive enzymatic test in many studies.The replacement of sensitive micro-organisms by different resistant species can have serious ecological consequences. Some species become extinct while others appear in bulging numbers. Adaptation of a community to a pollutant must be considered as the very process which disturbs a polluted ecosystem. The resistant micro-organisms often fail to perform specific ecological functions. The occurrence of resistant species can be used as an sensitive and ecologically relevant indicator for deterioration from environmental pollution. Persistent toxic effects on the microflora can be caused by zinc, cadmium and copper at concentration levels lower than European Community limits.Test with anaerobic sediment processes were orders of magnitude more sensitive for some clorinated aliphatic compounds than aquatic toxicity tests. The addition of a few mg zinc per kg soil can inhibit the more sensitive microbial processes (like chloroform or 4-chlorophenol degradation), whereas soil invertebrates and some plants are less sensitive to zinc.After evaluation of the tests, a novel method is described to derive soil and sediment quality guidelines using microbial toxicity tests. The results of single species tests with micro-organisms can be incorporated into the contemporary risk assessment method for higher organisms which is based on the extrapolation from single species tests to the protection of 95% of all species in an ecosystem. This method uses the No Observed Effect Concentrations (NOEC) of a number of toxicity tests to calculate a Hazardous Concentration 5% (HC5). The HC5 is calculated from more than 5 NOEC values. In analogy the Effect Concentration 10% (EC10) can be used to calculate the Dangerous Concentration 5% (DC5). The DC5 is calculated from more than 5 EC10 values. The DC5 should give protection to 95% of the microbial processes. The DC5 of a number of pollutants are calculated and compared with the HC5 values from the literature. Microbial toxicity tests can be used for risk assessment because micro-organisms are among the most sensitive organisms for the effects of pollutants.

Emerging insights into the genesis of epilepsy.

Epilepsies are a diverse collection of brain disorders that affect 1-2% of the population. Current therapies are unsatisfactory as they provide only symptomatic relief, are effective in only a subset of affected individuals, and are often accompanied by persistent toxic effects. It is hoped that insight into the cellular and molecular mechanisms of epileptogenesis will lead to new therapies, prevention, or even a cure. Emerging insights point to alterations of synaptic function and intrinsic properties of neurons as common mechanisms underlying the hyperexcitability in diverse forms of epilepsy.

ACUTE TOXICITY OF TOLUENE IN MALE AND FEMALE RATS:A SINGLE ORAL DOSE EXPOSURE 2-WEEK STUDY

The Agency for Toxic Substances and Disease Registry (ATSDR) has identified the oral route as the primary route of exposure, and neurotoxicity as the endpoint of concern, in the priority data needs for toluene. The acute oral neurotoxicity of toluene was investigated in male and female Sprague-Dawley rats. Dose selection was made relative to a benchmark dose (BD). The BD was defined as the maximum nonlethal neurotoxic dose and was examined by range-finding studies. The 3 oral (gavage) doses were 3.0 ml/kg (50% BD), 4.5 ml/kg (75% BD), and 6.0 ml/kg (100% BD). To characterize its neurotoxicity, a functional observational battery (FOB) and spontaneous motor activity (SMA) were measured on d 1 (2-3 h and 4-7 h postexposure times for FOB and SMA, respectively), 7, and 14 following toluene administration. The data indicate that on d 1, when compared with the saline controls, toluene-exposed rats (males at 4.5- and 6.0-ml/kg doses and females at 6.0-ml/kg dose) exhibited significantly ( p &lt;.05) greater horizontal (HZ) and stereotype (ST) motor activities. However, vertical (VT) activity was significantly ( p &lt; .01) depressed in both sexes at all doses. FOB data indicated that on d 1, toluene-treated male rats exhibited dose-dependent increases in abnormal gait (1/10 rats at 3-ml/kg, 2/ 10 rats at 4.5-ml/kg, and 7/10 rats at 6-ml/kg toluene doses). Abnormal gait was present in 5/10 females at 3 ml/kg and 6/10 females at both 4.5- and 6-ml/ kg toluene doses. The open-field rearing scores were lower than controls in all toluenetreated groups on d 1, and this was perhaps due to abnormal gait manifested by the rats. On d 7, toluene-treated males at 3- and 4.5-ml/kg doses exhibited significantly ( p &lt;.05) greater HZ and VT motor activities when compared with saline controls. Females rats showed HZ and ST activities very similar to controls, but there was a significant decrease ( p &lt;.05) in VT activity in all toluenetreated females on d 7 compared to saline controls. FOB data indicated that rearing scores were higher than control in all toluene-treated rats;however, gait was normal in all animals on d 7. By d 14, there were no significant differences, except VT activity in the female rats was still significantly depressed at 3- and 4.5-ml/kg doses. FOB results on d 14 were similar in toluene-treated rats to those of controls. The d 1 data show the acute immediate effects after administration of the solvent, whereas postexposure d 7 and 14 data depicted delayed or persistent toxic effects after a single exposure.

Significance and application of microbial toxicity tests in assessing ecotoxicological risks of contaminants in soil and sediment

Micro-organisms are vital for soil fertility and for the degradation of organic matter and pollutants in soils and sediments. Due to their function and ubiquitous presence micro-organisms can act as an environmentally very relevant indicator of pollution. Microbial tests should be used discriminatory for the establishment of soil and sediment quality guidelines. This review gives an evaluation of microbial toxicity tests and a novel method to derive quality guidelines. Long term microbial tests are generally less sensitive than short term tests. The toxic effects can be obscured by the activity of a few resistant micro-organisms, when for example soil respiration is used as a sum parameter during a long incubation period. Mineralization tests with high substrate concentrations which enable growth, are less sensitive than similar tests with low concentrations of substrate. The latter tests are more relevant for natural ecosystems. The often applied microbial toxicity tests can be categorized as single species tests, biomass measurements, carbon and nitrogen transformations, enzymatic tests and tests measuring changes in microbial diversity. Comparisons between tests can only be indicative because the relative sensitivity depends on the toxicants and soils used. The respiration rate per unit of biomass is a more sensitive indicator of toxic effects than the respiration rate or the amount of biomass alone. The autotrophic nitrification and acetylene reduction tests can be sensitive when short incubation times are used. The nitrogen mineralization, denitrification and many enzymatic tests are often not very sensitive. The urease activity is a relatively sensitive enzymatic test in many studies. The replacement of sensitive micro-organisms by different resistant species can have serious ecological consequences. Some species become extinct while others appear in bulging numbers. Adaptation of a community to a pollutant must be considered as the very process which disturbs a polluted ecosystem. The resistant micro-organisms often fail to perform specific ecological functions. The occurrence of resistant species can be used as an sensitive and ecologically relevant indicator for deterioration from environmental pollution. Persistent toxic effects on the microflora can be caused by zinc, cadmium and copper at concentration levels lower than European Community limits. Test with anaerobic sediment processes were orders of magnitude more sensitive for some clorinated aliphatic compounds than aquatic toxicity tests. The addition of a few mg zinc per kg soil can inhibit the more sensitive microbial processes (like chloroform or 4-chlorophenol degradation), whereas soil invertebrates and some plants are less sensitive to zinc. After evaluation of the tests, a novel method is described to derive soil and sediment quality guidelines using microbial toxicity tests. The results of single species tests with micro-organisms can be incorporated into the contemporary risk assessment method for higher organisms which is based on the extrapolation from single species tests to the protection of 95% of all species in an ecosystem. This method uses the No Observed Effect Concentrations (NOEC) of a number of toxicity tests to calculate a Hazardous Concentration 5% (HC5). The HC5 is calculated from more than 5 NOEC values. In analogy the Effect Concentration 10% (EC10) can be used to calculate the Dangerous Concentration 5% (DC5). The DC5 is calculated from more than 5 EC10 values. The DC5 should give protection to 95% of the microbial processes. The DC5 of a number of pollutants are calculated and compared with the HC5 values from the literature. Microbial toxicity tests can be used for risk assessment because micro-organisms are among the most sensitive organisms for the effects of pollutants.

The delayed long-term effects of chemicals following neonatal exposure in laboratory animals

The increased sensitivity in neonates to the effects of certain chemicals is attributable to the immaturity of detoxifying and excretory processes as well as to the interference of the chemical with postnatal development. An adverse effect of a chemical may appear in adulthood, even though it was induced in the postnatal period, because of the late development of the function affected, e.g. reproduction or slowly progressing pathological changes. Examples of neonatally acquired effects that have been transmitted to the next generation are presented. Adaptation of the protocol for reproduction toxicology studies is suggested for the detection of these delayed and persistent toxic effects.