No free rides: management of toxicities of novel immunotherapies in ALL, including financial.

Therapeutic options for acute lymphoblastic leukemia, especially in the relapsed/refractory setting, have expanded significantly in recent times. However, this comes at the cost of toxicities: medical as well as financial. We highlight some of the unique toxicities associated with the novel agents to apprise our readers about what to expect, how to recognize them, and how to manage these toxicities. One of the toxicities seen with inotuzumab, a CD22 antibody drug conjugate, is sinusoidal obstruction syndrome, which can be fatal in >80% of patients if associated with multiorgan failure. Blinatumomab, a monoclonal antibody targeting CD19, is associated with cytokine release syndrome (CRS) and neurotoxicity, both of which require prompt recognition and management primarily with corticosteroids. CRS and neurotoxicity are more common and more severe with chimeric antigen receptor T-cell therapy (CAR-T). The fact that CAR-T cannot be discontinued on demand adds a layer of complexity to the management of related toxicities of this therapy. Tocilizumab, an interleukin-6 receptor blocker, is used to treat severe CRS from CAR-T, whereas corticosteroids remain the mainstay for neurotoxicity management. Although effective, these drugs carry a high price tag, and we review the available data on cost-effectiveness of these agents, keeping in mind that median follow-up on most of these studies is limited and that long-term data on durability of response remain to be seen.

Neurotoxicity and LSD treatment: a follow-up study of 151 patients in Denmark.

LSD was introduced in psychiatry in the 1950s. Between 1960 and 1973, nearly 400 patients were treated with LSD in Denmark. By 1964, one homicide, two suicides and four suicide attempts had been reported. In 1986 the Danish LSD Damages Law was passed after complaints by only one patient. According to the Law, all 154 applicants received financial compensation for LSD-inflicted harm. The Danish State Archives has preserved the case material of 151 of the 154 applicants. Most of the patients suffered from severe side effects of the LSD treatment many years afterwards. In particular, two-thirds of the patients had flashbacks. With the recent interest in LSD therapy, we should consider the neurotoxic potential of LSD.

Chemotherapy-induced peripheral neurotoxicity (CIPN): what we need and what we know.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most frequent and severe long-term side effects of cancer chemotherapy. Preclinical and clinical studies have extensively investigated CIPN searching for effective strategies to limit its severity or to treat CIPN-related impairment, but the results have been disappointing. Among the reasons for this failure are methodological flaws in both preclinical and clinical investigations. Their successful resolution might provide a brighter perspective for future studies. Among the several neurotoxic chemotherapy drugs, oxaliplatin may offer a clear example of a methodological approach eventually leading to successful clinical trials. However, the same considerations apply to the other neurotoxic agents and, although frequently neglected, also to the new "targeted" agents.

Cost of detecting a chronic solvent encephalopathy case by screening.

BACKGROUND: Stepwise screening of chronic solvent encephalopathy (CSE), using a postal survey followed by clinical examinations, has been shown to detect symptomatic exposed workers with an occupational disease even in industrialized countries with long-term, but relatively low dose exposure. Previous studies have suggested under-detection and late recognition of CSE, when work ability is already markedly reduced. AIMS: The aim was to estimate the cost of detecting one new CSE case by screening and diagnostics, to estimate the career extension needed to cover the cost of screening, and to study the work ability of the CSE cases. METHODS: A financial analysis of stepwise postal CSE screening followed by clinical examinations (SPC screening) was carried out, and the results were compared to those of the group of CSE cases referred to the Finnish Institute of Occupational Health (FIOH) by the existing national practice of occupational health services (OHS screening). The work ability of the SPC screened CSE cases was studied in relation to the retirement rate and the Work Ability Index (WAI). RESULTS: An analysis of the costs of detecting a new verified CSE case revealed them to be approximately 16,500 USD. Using the mean monthly wages in the fields concerned, we showed that if a worker is able to continue working for four months longer, the screening covers these costs. The cost for detecting a CSE case was twenty times higher with the existing OHS routine, when actualized according to the national guidelines. A CSE case detected at an early stage enables occupational rehabilitation or measures to decrease solvent exposure. The retirement rate of the SPC screened CSE cases was significantly lower than that of the OHS screened cases (6.7% vs. 74%). The results suggest that SPC screening detects patients at an earlier stage of the disease, when they are still capable of working. Their WAI sores were nevertheless lower than those of the general population, implying a greater risk of becoming excluded from the labor market. CONCLUSION: Stepwise screening of CSE using a postal survey followed by clinical examinations detected new CSE cases at lower costs than existing OHS screening routines. Detecting CSE at an early stage prevents early retirement.

Future trends in environmental mercury concentrations: implications for prevention strategies.

In their new paper, Bellanger and coauthors show substantial economic impacts to the EU from neurocognitive impairment associated with methylmercury (MeHg) exposures. The main source of MeHg exposure is seafood consumption, including many marine species harvested from the global oceans. Fish, birds and other wildlife are also susceptible to the impacts of MeHg and already exceed toxicological thresholds in vulnerable regions like the Arctic. Most future emissions scenarios project a growth or stabilization of anthropogenic mercury releases relative to present-day levels. At these emissions levels, inputs of mercury to ecosystems are expected to increase substantially in the future, in part due to growth in the legacy reservoirs of mercury in oceanic and terrestrial ecosystems. Seawater mercury concentration trajectories in areas such as the North Pacific Ocean that supply large quantities of marine fish to the global seafood market are projected to increase by more than 50% by 2050. Fish mercury levels and subsequent human and biological exposures are likely to also increase because production of MeHg in ocean ecosystems is driven by the supply of available inorganic mercury, among other factors. Analyses that only consider changes in primary anthropogenic emissions are likely to underestimate the severity of future deposition and concentration increases associated with growth in mercury reservoirs in the land and ocean. We therefore recommend that future policy analyses consider the fully coupled interactions among short and long-lived reservoirs of mercury in the atmosphere, ocean, and terrestrial ecosystems. Aggressive anthropogenic emission reductions are needed to reduce MeHg exposures and associated health impacts on humans and wildlife and protect the integrity of one of the last wild-food sources globally. In the near-term, public health advice on safe fish consumption choices such as smaller species, younger fish, and harvests from relatively unpolluted ecosystems is needed to minimize exposure risks.

Economic benefits of methylmercury exposure control in Europe: monetary value of neurotoxicity prevention.

BACKGROUND: Due to global mercury pollution and the adverse health effects of prenatal exposure to methylmercury (MeHg), an assessment of the economic benefits of prevented developmental neurotoxicity is necessary for any cost-benefit analysis. METHODS: Distributions of hair-Hg concentrations among women of reproductive age were obtained from the DEMOCOPHES project (1,875 subjects in 17 countries) and literature data (6,820 subjects from 8 countries). The exposures were assumed to comply with log-normal distributions. Neurotoxicity effects were estimated from a linear dose-response function with a slope of 0.465 Intelligence Quotient (IQ) point reduction per µg/g increase in the maternal hair-Hg concentration during pregnancy, assuming no deficits below a hair-Hg limit of 0.58 µg/g thought to be safe. A logarithmic IQ response was used in sensitivity analyses. The estimated IQ benefit cost was based on lifetime income, adjusted for purchasing power parity. RESULTS: The hair-mercury concentrations were the highest in Southern Europe and lowest in Eastern Europe. The results suggest that, within the EU, more than 1.8 million children are born every year with MeHg exposures above the limit of 0.58 µg/g, and about 200,000 births exceed a higher limit of 2.5 µg/g proposed by the World Health Organization (WHO). The total annual benefits of exposure prevention within the EU were estimated at more than 600,000 IQ points per year, corresponding to a total economic benefit between €8,000 million and €9,000 million per year. About four-fold higher values were obtained when using the logarithmic response function, while adjustment for productivity resulted in slightly lower total benefits. These calculations do not include the less tangible advantages of protecting brain development against neurotoxicity or any other adverse effects. CONCLUSIONS: These estimates document that efforts to combat mercury pollution and to reduce MeHg exposures will have very substantial economic benefits in Europe, mainly in southern countries. Some data may not be entirely representative, some countries were not covered, and anticipated changes in mercury pollution all suggest a need for extended biomonitoring of human MeHg exposure.

Persistent failure of the COIDA system to compensate occupational disease in South Africa.

Cases of occupational disease, solvent encephalopathy and occupational asthma are used to exemplify failings of the workers' compensation system in South Africa, that include delays in processing claims, non-response to requests for information, and inadequate assessment of disability. These and other systemic deficiencies in administration of the Compensation for Occupational Injuries and Diseases Act of 1993 (COIDA) reduce access by workers with occupational disease to private medical care, and shift costs to workers and to public sector medical care. Another unintended effect is to promote underreporting of occupational disease by employers and medical practitioners. Reforms have been tried or proposed over the years, including decentralisation of medical assessment to specialised units, which showed promise but were closed. Improved annual performance reporting by the Compensation Commissioner on the processing of occupational disease claims would promote greater public accountability. Given the perennial failings of the system, a debate on outsourcing or partial privatisation of COIDA's functions is due.

Approaches to extrapolating animal toxicity data on organic solvents to public health.

Synthesizing information about the acute neurotoxicity of organic solvents into predictive relationships between exposure and effect in humans is difficult because (1) data are usually derived from experimental animals whose sensitivity to the chemical relative to humans is unknown; (2) the specific endpoints measured in laboratory animals seldom translate into effects of concern in humans; and (3) the mode of action of the chemical is rarely understood. We sought to develop approaches to estimate the hazard and cost of exposure to organic solvents, focusing on the acute behavioral effects of toluene in rats and humans. Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data suggested that a 10% change in rat avoidance behavior occurs at a blood concentration of toluene 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. In contrast, our in vitro studies of nicotinic acetylcholine receptors indicated that human and rat receptors do not differ in sensitivity to toluene. Analysis of other dose-response relationships for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific endpoints measured in the two species rather than by inherent differences in sensitivity to toluene. We also explored the hypothesis that dose-equivalence relationships may be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs are estimatable, may be used as a benchmark effect for estimating the monetary benefits of controlling exposure to organic solvents. This dose-equivalence method is applicable for solvents because this set of data fulfills three important assumptions about equivalence relationships based on a single effect: (1) a common dose metric (concentration of the chemical in the brain); (2) a common effect to provide a linking variable (choice reaction time); and (3) a common mode of action (interference with neuronal ion channel function).

Economic implications of manganese neurotoxicity.

Manganese neurotoxicity is linked primarily to inhalation exposure, and its clinical features are almost totally based on high doses, such as those experienced by miners. Manifestations of lower level exposures can take two forms. One is the appearance of neurobehavioral deficits. A second, equally subtle, form is as a promoter, borrowing the term used in carcinogenesis, of neurodegenerative disease. Such low-level environmental exposures may be more potent than expected if they occur as ultrafine particles able to penetrate directly into the brain. The neurological disorder linked most closely to manganese is Parkinson's disease (PD). Although most observers recognize that the features of manganese-induced parkinsonism differ from those of idiopathic PD, they overlap considerably. The overlaps should be expected because the underlying lesions, although distinguishable, are closely linked because they belong to structures with complex interdependent circuitry. Such interdependence makes it feasible to undertake an analysis of how manganese neurotoxicity might elevate the risks of PD. A relatively small increment in risk, expressed as a leftward shift in the age prevalence of PD, incurs significant economic costs.