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LLIN & ACT: failure, disaster, genocide ?

August 7, 2015 - 18:23 -- Pierre Lutgen

Although resistance is increasing at an exponential rate, synthetic pyrethroids remain the only recommended insecticides for mosquito nets. One may wonder what the reasons behind this monopoly are : incompetence or business ?

The resistance to deltamethrin takes catastrophic proportions. There is currently no malaria-affected country in Africa that is free of insecticide-resistant mosquitoes Recently a research team in Benin tried to assess the impact of resistance on the effectiveness of LLINs. They prospected 39 localities with breeding sites and found that in all these resistance to deltmethrin was high. Their study became futile andd impossible (A Sovi et al., BMC Infectuous Diseases, 2014, 14-103). Similar results were found in a recent study in Kenya. All field-collected Anopheles samples showed high resistance to deltamethrin and permethrin (H Kawada et al., Parasites and Vectors, 2014, 7 :208). A similar rise in malaria frequency and death rate was also noted in Cameroon after the massive distribution of 8 000 000 LLINS in 2013. A very recent paper from Mozambique clearly documents that LLINs no longer effectively kill the highly resistant Anopheles (KT Glunt et al., Malaria Journal 2015, 14 :298).

Researchers in Mali have discovered a new hybrid mosquito -- a so-called "super mosquito" -- that is unaffected by bed nets treated with insecticides. Scientists with the University of California say that insecticides have altered the evolutionary landscape, encouraging the sexual cooperation of two previously isolated mosquito species. (G Lanzaro, Proc Nat Acad Sciences, Jan 6, 2015).

ANTAGONISMS BETWEEN LLIN AND ACT

A recent paper from Guinea-Bissau is intriguing (J Ursing et al., PlosOne, 2014, 9-7, e101167). Between 1995 and 2007 a 8 fold decrease of malaria incidence was noticed. This was probably related to an increased use of ITNs and an efficacious high-dose chloroquine treatment. In 2008 ACTs were introduced. Contrary to expectations the number of children with clinical malaria started to increase soon after the introduction of artemether-lumefantrine. In older children an up to 45 fold increase of uncomplicated malaria occurred. Quinine is now preferably given to children.

In Senegal at the village of Dielmo incidence density of malaria attacks had decreased after the application of ACTs in 2006 and the broad use of ITNs. 2 years after the introductions of LLINs there was an unexpected and severe rebound. In older children and adults, malaria morbidity became even higher than before the deployment of LLINs.The indirect effects on clinical immunity might be more substantial with ACTs than with chloroquine (JF Trape et al., The Lancet, 2011, 11, 925-32).

At the Island of Sao Tomé and Principe a decrease in malaria morbidity and mortality was noticed after the introduction of ACTs and ITNs in 2004. But in 2009 an unexpected threefold morbidity increase was noticed (Pei-Wen Lee et al., Malaria Journal 2010, 9:264) after the introduction of LLINs as if the ACTs had lost their healing power.

POSSIBLE EXPLANATIONS : CD4 and CYP3A4

An immunotoxicological study from Egypt shows that deltamethrin decreases CD4 + CD8 after a few days of exposure (AM Emara et al., Inhal Toxicol, 2007 19, 997-1009). The lymphocytes are the main indicators used for immunodeficiency and HIV.

At 100 microM deltamethrin a 2-3 fold induction of CYP1A1 and CYP2B6 was observed, while at the same time an approximately 25-fold induction of CYP3A4 was noted (P Das et al., Drug Metabol Drug Interact. 2008;23(3-4):211-36.) Another study found a 35-fold increase for CYP3A4 by cypermethrin (K Abass et al., Toxicology 2012 294 17-26). Higher CYP 3A4 and CYP 2B6 lead to a faster metabolism of artemisin and derivatives and will thus affect efficiency of ACTs. 10 papers from 7 African countries describe artemisinin resistance in Africa, a fact which is ignored in press releases from WHO claiming victory.

Effects of exposure to deltamethrin on host resistance to malaria infection (Plasmodium berghei) were examined in Swiss albino male mice. Four doses of deltamethrin were initially tested with two non-lethal doses, 5 and 10 mg/kg, selected for more detailed study (Ch Suwanchaichinda et al., Environ Toxicol and Pharmacol. 2005, 20, 77-82). Survival times of infected mice did not change when they were exposed to the compound for 14 days before the infection. However, survival times were shortened when they were exposed to the compound, particularly at the high-dose, after and during the initial infection. Percent parasitemia of these animals elevated faster than that of the control. Deltamethrin exposure also caused alteration of white blood cell populations. Specifically, total white blood cell and lymphocyte counts significantly decreased in the high-dose treated mice.

Cellular and humoral immunity play a crucial role in host defense against malaria. Adverse effects by deltamethrin are reported in several epidemiological and experimental studies. In the case of Aedes aegyptii, in an experiment covering 16 generations tolerance level to deltamethrin was found to increase by 333,83 folds in terms of its LC50 values (J Urmila et al. Indian J Med Res 2001, 113, 103-7).).

There was also a claim that ITNs would reduce the transmission by vector control and so decreasing the spread of antimarial drug resistance. A study from Kenya however showed that ITNs had no apparent effect on the existing high prevalence of mutations or on the prevalence of genes associated with malaria drug resistance to chloroquine or sulfadoxine-pyrimethamine (M Shah et al., PlosONE, 2011, 6-11, e26746).

THE INCREDIBLE TOXICITY OF DELTAMETHRIN

Clinical manifestations of acute deltamethrin poisoning have been documented in occupationally and accidentally exposed cases (He et al., 1989; Zhang et al., 1991). Deltamethrin can elicit neurotoxicity by inducing neuronal apoptosis both in vivo and in vitro.

Deltamethrin induces a dysfunction of the blood-brain barrier in the developing brain of neonates. Inhalation of the pesticide can cause clinical, biochemical and neurological changes during organogenesis (C Sinha et al., Int J Dev Neurosci, 2004, 22, 31-37).

An EPA review paper on developmental and reproductive toxicity of deltamethrin was published recently (OEHHA, October 2012). Several studies examining the effect of deltamethrin exposure on the male reproductive system are available. These include studies in laboratory species such as the mouse, rat and rabbit. Adverse effects noted in the studies are a decrease in live sperm and plasma testosterone levels. Degenerative changes in testicular and accessory gland structures were also noted. Three studies reported adverse female reproductive effects. In a two-generation rat reproductive study, parental females exposed to 320 ppm in diet demonstrated a decrease in the absolute mean weight for the non-gravid uterus. There was a smaller number of pups in groups that received higher doses of deltamethrin than in the control groups. In rabbits exposed to deltamethrin a decrease in libido, ejaculate volume and sperm concentration was noticed.

It is not the purpose of this document to address the toxicity of pyrethroids to other animals and fishes, unless this has an impact on human wellbeing. Aquatic ecosystems are particularly vulnerable to pyrethroids. They are toxic to all fish species, trout at LC50 0f 0,00018 mg/L. As bednets are often used for fishing this may kill all estuarian life. Pyrethroids are extremily toxic to bees. The impact on the human food chain in poor countries may be dramatic.