ECOTOXICITY OF PARASITICIDES IN THE UK
most herbivores, extensive metabolism of the ivermectin does not occur, with up to 98% of the parent drug being excreted as non- metabolised drug in the faeces (Horvat et al., 2012 ; Lumaret & Errouissi, 2002 ). Drug residues in cattle faeces have been shown in several
studies to have toxic effects on dung- degrading insects (Finch et al., 2020 ; Floate et al., 2005 ; Junco et al., 2021 ). Freshwater spe- cies such as Daphnia magna and fish also appear to be particularly sensitive (Halley et al., 1993 ). Avermectins appear to be less toxic to earthworms and birds (Erzen et al., 2005 ), with a laboratory study in earthworms concluding that neither ivermectin nor fenbendazole (and their metabolites) in cattle faeces have any adverse effects on the survival and growth of the dung- feeding earthworm Lumbricius terrestris (Svendsen et al., 2002 ). Ivermectin has been shown to be excreted in cattle dung at
concentrations that are toxic to insects for 28, 35 and at least 49 days after treatment with pour- on, injectable and sustained- release bolus formulations, respectively (Herd et al., 1996 ). In horses, the maximum concentration in faeces peaked at 2.5 days post- administration in one study (Pérez et al., 2001 ), and ivermec- tin faecal concentrations remained above the detectable level for 40 days. Ivermectin is eliminated more quickly than moxidectin, with 90% of the total drug excreted in horse faeces by 4 days post- treatment, whereas it takes 8 days for equivalent excretion of moxidectin (Pérez et al., 2001 ). Once excreted, persistence in cattle faeces can be up to
180 days, depending on the environmental conditions (Jean- Pierre et al., 1993 ; Suarez et al., 2003 ). Ivermectin has been shown to be immobile in soil, but is rapidly photodegraded in water (degradation half- life in the summer may be less than 0.5 days), and aerobically de- graded in soil (degradation half- life 7–14 days) to less bioactive com- pounds (Halley et al., 1993 ). High affinity of ivermectin to organic matter in faeces and soil as well as its relative insolubility in water hopefully limits its leaching into groundwater (Erzen et al., 2005 ). In addition to the toxicity of ivermectin for insects and aquatic
organisms, the drug can also cause neurotoxicity in certain collie and collie- type dogs. Sensitivity to ivermectin in a subpopulation of collies is associated with a deletion mutation in the multi- drug resistance gene ( MDR1 gene), which encodes a large transmem- brane protein forming an integral part of the blood–brain barrier, p- glycoprotein (Mealey et al., 2001 ).
MOXIDECTIN
As with ivermectin, the maximum concentration of moxidectin (another macrocyclic lactone)
in faeces is reached at 2.5 days
after oral administration in horses (Pérez et al., 2001 ). However, moxidectin elimination is slower than for ivermectin, with the concentration in horse faeces remaining above the detectable level for 75 days (Pérez et al., 2001 ). Studies suggest that moxidectin is far less toxic to natural invertebrates than ivermectin (Finch et al., 2020 ; Schumacher &
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Taintor, 2008 ). When horses are treated with ivermectin, disper- sal of manure by decomposer insects is markedly delayed (Herd et al., 1993 ). In contrast, moxidectin is unlikely to have such a dele- terious effect on the faecal fauna (Floate et al., 2005 ; Herd, 1995 ; Kadiri et al., 1999 ; Lumaret & Errouissi, 2002 ), with little to no effect on growth and reproduction of various dung- colonising insects (Doherty et al., 1994 ; Mackenzie et al., 2022 ; Strong & Wall, 1994 ). The systematic patterns of variability in toxicity in ivermectin and moxidectin can be attributed largely to differences in the toxicity of active ingredients, their formulation/lipophilicity, and/or the susceptibility of the insect species (Floate et al., 2005 ). Results from various studies suggest that the macrocyclic lactones can be ranked in decreasing order of toxicity to dung- dwelling in- sects as: doramectin > ivermectin > moxidectin. Moxidectin is a milbemycin, whereas doramectin and ivermectin are avermectins (Floate et al., 2005 ).
FENBENDAZOLE
Fenbendazole appears to be far less toxic to natural invertebrates than moxidectin and avermectins. A study comparing cattle treated with sustained- release boluses of either ivermectin or fenbendazole found that ivermectin exhibited significant toxic effects on key dung- colonising families of insects, whereas fenbendazole showed no such toxic effects (Strong et al., 1996 ). A laboratory study in earthworms similarly concluded that fenbendazole in cattle faeces has no adverse effects on the survival and growth of the dung- feeding earthworm L. terrestris (Svendsen et al., 2002 ), although it should be noted that recorded survival was slightly lower in the fenbendazole- treated group compared to the control group in this study. Toxicity to fenbendazole has been found in a number of
aquatic organisms, with the crustacean, D. magna , appearing par- ticularly sensitive (Wagil et al., 2015 ). According to their chemi- cal structure, benzimidazoles may also affect dung fungi (Horvat et al., 2012 ). Fenbendazole has been found in groundwater sam- ples in the Republic of Ireland (Mooney et al., 2021 ), but with a median concentration several orders of magnitude lower than the toxic concentration for D. magna (Mooney et al., 2021 ; Wagil et al., 2015 ). Although higher concentrations of the related com- pound, flubendazole, have been demonstrated in leachates from fields fertilised with organic fertilisers, flubendazole appears to rapidly degrade during manure storage and it is therefore diffi- cult to define the risk to soil- and water- dwelling organisms (Weiss et al., 2008 ). Fenbendazole, as with the other benzimidazoles, is metabo-
lised more extensively before excretion in horses (McKellar, 1997 ). Fenbendazole is transformed into active fenbendazole sulfoxide (oxfendazole) (Horvat et al., 2012 ) and is excreted mainly via the faeces (Wardhaugh, 2005 ), with peak faecal excretion occurring at approximately 24 h following oral administration in horses (McKellar et al., 2002 ).
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