Chlorine dioxide and sodium chlorite toxicity

The oral and inhalation toxicity of chlorine dioxide gas, and its The oral and inhalation toxicity of chlorine dioxide gas, and its curing agent and reducing product, the chlorite ion, have been characterized in numerous studies published in the last decades in scientific literature.

The first studies were promoted by the USA-EPA (US Environmental Protection Agency), in order to determine the safety levels for the purification of water for urban consumption. In this sense, the EPA has been commissioning investigations and issuing toxicological reports since the 80s, which have made it possible to characterize the toxicological profile and safety levels, which have been a reference for the rest of North American agencies such as the Department of Health (ASTDR) and the FDA. and by extension by other international agencies that have echoed said technical reports.

It should be noted that in them it is assumed that the experimental toxicity data of chlorine dioxide are by approximation extensible to chlorite, and vice versa, given the high reactivity of chlorine dioxide, and its rapid reduction to chlorite in an aqueous medium, for which the latter is considered a possible pollutant by-product resulting from disinfection with chlorine dioxide, together with chlorates and perchlorates. For example, in a toxicological review on these substances issued by the US-EPA in 2000 (Environmental Protection Agency) 1, a review of experimental data was made coming mostly from animal tests2. From successive reviews, and finally based on an animal2.

Based on successive reviews, and finally based on a study commissioned by the EPA to determine long-term toxicity, and several generations of mice including sensitive groups (during heat, lactation and parturition) (Gill et al., 2000) 3, The environmental agency and subsequently the US Department of Health4 determined the experimental toxicological levels for chronic oral exposure (> 90 days) to chlorine dioxide and chlorite. These are: a NOAEL of 3 mg / kg / day of chlorite-equivalent ion (non observed adverse effects level or the maximum dose at which no adverse effects have been observed) and a LOAEL of 5,7 mg / kg / day (lowestobserved adverse effects level, the lowest dose at which some toxicity was observed).

That is, assuming an adult weight of 70 kg, the daily amount with which the EPA found no adverse effect for oral consumption would be 210 mg of chlorine dioxide (or equivalent chlorite ion) per day. Based on these two toxicity parameters (NOAEL and LOAEL), obtained experimentally from animal tests, the EPA subsequently makes various downward adjustments to derive from them the reference dose (RfD) for chronic toxicity in humans (> 90 days) of these substances5.

For this, an uncertainty factor of 3 is applied to the experimental NOAEL value of 100 mg / kg / day, resulting in a reference value of RfD = 0,03 mg / kg / day. This RfD does not come directly from any experimentation, and its purpose is to have a wide margin of safety for habitual human consumption, in exchange for high uncertainty.

This factor includes an uncertainty of 1/10 for the possible interspecific difference with animals, and another added factor of 1/10 for the possible human variability. However, the RfD established by the EPA refers to the dose of chlorine dioxide to be used for disinfection of drinking water, it refers to the dose of chlorine dioxide to be used for the disinfection of drinking water intended for urban consumption. The EPA itself defines the scope of application of this parameter: “In general, RfD is an estimate (with uncertainty covering perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that probably does not have an appreciable risk of effects. deleterious THROUGHOUT LIFE.

It should not be categorically concluded that all doses below the RfD are "acceptable" (or will be risk-free) and that all doses above the RfD are "unacceptable" (or will lead to adverse effects). " That is, RfD cannot be considered applicable risk limits for therapeutic uses and acute or subchronic exposures (<90 days) to groups of patients in controlled situations. While these limits are not determined experimentally in properly controlled clinical trials, the toxicity reference should be the NOAEL and LOAEL experimental levels and not the EPA RfDs for community-use drinking water.

Human studies

Studies in humans The few clinical studies published on tests to determine the toxicity of chlorine dioxide in humans suggest, however, that an uncertainty factor of 100 to determine the RfD would be overestimating the real toxicity in humans by more than an order of magnitude, and that the levels of NOAEL and LOAEL toxicity from animal studies reflect much more closely the toxicity observed in human trials. Thus, for example, in the first comprehensive clinical trial commissioned by the EPA (Lubbers et al, 1981) 6, the absence of chronic toxicity was determined at levels of 5 mg / day (equivalent to 0,07 mg / kg / day) and acute toxicity at 24 mg / l (equivalent to 0,34 mg / kg / day). Subsequently, some controlled clinical trials have been published based on the administration of formulations of different names (NP001, WF10, TCDO), but whose active principle is sodium chlorite. In a Phase I clinical trial to characterize the acute toxicity of pure sodium chlorite (NP001) (Miller et al, 2014) 7 increasing single doses of (0.2, 0.8, 1.6 and 3.2 mg / kg / day) were used. All doses were generally safe and well tolerated, and there were no serious adverse events or variations in relevant clinical parameters. In other Phase II trials with ALS patients with amyotrophic lateral sclerosis (Milleret al, 2015) 8. Sodium was administered in a single daily dose intravenously, intermittently for 6 months. The cycles lasted 3 to 5 consecutive days (subacute exposure), administering one cycle per month. The study resulted in Class I evidence that sodium chlorite was “generally safe and well tolerated”, except for generally safe and well-tolerated infusion site pain ”, except for infusion site pain and transient dizziness. In conclusion, based on the data from these trials, it can be stated that the maximum dose without adverse reactions (NOAEL) in subacute applications (3-5 days) can be established at 2mg / kg / day, while adverse effects could be observed from of a LOAEL of 4,2mg / kg / day.

Toxicity of potentially therapeutic doses against COVID19

Toxicity of potentially therapeutic doses against COVID19 There are still no published clinical trials on the therapeutic application of chlorite or chlorine dioxide against COVID19. If we take as a reference the oral communications made public by medical personnel associated with COMUSAV9, and the only medical report available to date, made public online by the AEMEMI10 of Ecuador, the therapeutic doses that are being recommended for the adjuvant treatment of COVID-19 in Latin America are well below the experimentally determined minimum toxicity limits (NOAEL and LOAEL) 11. Figure 2 shows the minimum dosages detected in different studies (in red), as well as the doses with therapeutic potential where it is very unlikely that adverse reactions will be detected in subacute applications (> 28 days). For reference, the reference dose (RfD) and the maximum limit for chlorine dioxide disinfectant and chlorite contaminant established by the EPA for MDRL drinking water (in blue) are also shown. As can be seen, below the NOAEL of 3 mg / Kg / day there are no experimental data that allow us to affirm that there is a risk to health. The horizontal scale reflects the estimated daily doses for a 70kg adult. In both figures 1 and 2 estimates for a 70kg adult are not included. Both figures 1 and 2 do not include the cited human studies (Miller et al, 2015; 2014), whose NOAEL and LOAEL levels would be below those determined by the EPA.

For example, and taking as reference the potentially therapeutic doses used in the AEMEMI study of Ecuador, the total daily dose administered orally was between 2-2 mg / kg / day, well below the minimum toxicity levels described in this report. In conclusion, there is no experimental evidence available to confirm that at doses below 0,4 mg / kg / day there is a risk of adverse reactions or variations in relevant clinical parameters. This dose is equivalent to 0,9 mg of chlorine dioxide or chlorite per day for an average adult weighing 3 kg. The minimum observable toxicity would be expected from 210mg / kg / day, equivalent to 70mg / day for an average adult human being.

Important note: Chlorine dioxide toxicity estimates Important note: Chlorine dioxide toxicity estimates made in this report assume the use of a product of high purity, properly stabilized and / or preserved, as well as with the proper concentration controls prior to its use. administration and analysis of impurities and possible degradation by-products that may present added toxicity. The statements in this report are the responsibility of the author and do not involve any official position of the University of Almeria.