These previous studies with aquatic organisms demonstrated toxic effects derived
from insecticidal enantiomers 1R-cis/trans (Type I pyrethroids) and 1R-cis/trans-αS
(Type II pyrethroids), while endocrine disruption was induced by enantiomers with
low or no insecticidal activity (1S-cis/trans). In addition, the adverse effects shown
with zebrafish assays point to the need for further studies on the potential toxicity of
specific enantiomers in humans, since this organism has been used as a model of
human cellular metabolism [64, 65].
3.3 Mammals: In Vivo and In Vitro Tests
Among the cis-enantiomers of Type I pyrethroids, 1R-cis are more stable and
present toxicity to mammals, whereas among trans-enantiomers, 1R-trans does not
present toxicity in acute assays [8, 15, 66]. Exceptions to this rule occur with
1R-cis-phenothrin that do not present toxic effects to mammals and 1R-transethanomethrin, which present high neurotoxicity [53]. In Type II pyrethroids,
alpha-cyano carbon with the S-configuration presents greater neurotoxicity to
mammals than its epimer [15].
In mammals, the main route of detoxification of trans-isomers is through hydrolysis, while the major metabolic process of cis-isomers is oxidation [67]. In relation
to the acid group, ester hydrolysis greatly depends on the spatial configuration of C-1
and C-3 chiral carbons, with 1R-trans and 1S-trans enantiomers undergoing high
metabolization rates compared to 1R-cis and 1S-cis enantiomers. In the alcohol
portion of the molecule, hydrolysis of esters of primary alcohols (Type I pyrethroids)
is faster than esters of secondary alcohols (Type II pyrethroids) [68]. Hepatic
enzymes, such as carboxylesterases, are important in pyrethroid metabolism. Selective metabolization of trans-permethrin through human pyrethroid-hydrolysing
carboxylesterases (hCE-1 and hCE-2) was observed compared to the hydrolysis
rate of cis-permethrin [31].
In humans, permethrin oxidation occurs through metabolization by cytochrome
P450 enzymes (CYP450) and by alcohol and aldehyde dehydrogenases [69]. The
main metabolites from hydrolysis and oxidation reactions are cis-trans-3-(2,2
dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis-trans-DCCA),
3-phenoxybenzyl alcohol (3-PBAlc), 3-phenoxybenzyl aldehyde (3-PBAld) and
3-phenoxybenzoic acid (3-PBA) [66, 69].
Pyrethroids have been associated with a wide range of toxicological effects upon
the reproductive function of mammals [70–72]. In assays with adult male mice
exposed by oral administration to permethrin, only the cis-isomers resulted in wide
reproductive adverse effects with reduction of epididymal sperm count, sperm
motility and testosterone levels in testes [73]. On the other hand, no adverse effects
on reproductive function were observed after trans-permethrin administration. In
addition, the presence of the urinary metabolite 3-PBA in trans-permethrin treatment
was up to sevenfold higher compared to a treatment by its isomeric pairs
(cis-isomers). Additionally, the hepatic microsomal hydrolase activity for the
162
C. E. T. Parente et al.
from insecticidal enantiomers 1R-cis/trans (Type I pyrethroids) and 1R-cis/trans-αS
(Type II pyrethroids), while endocrine disruption was induced by enantiomers with
low or no insecticidal activity (1S-cis/trans). In addition, the adverse effects shown
with zebrafish assays point to the need for further studies on the potential toxicity of
specific enantiomers in humans, since this organism has been used as a model of
human cellular metabolism [64, 65].
3.3 Mammals: In Vivo and In Vitro Tests
Among the cis-enantiomers of Type I pyrethroids, 1R-cis are more stable and
present toxicity to mammals, whereas among trans-enantiomers, 1R-trans does not
present toxicity in acute assays [8, 15, 66]. Exceptions to this rule occur with
1R-cis-phenothrin that do not present toxic effects to mammals and 1R-transethanomethrin, which present high neurotoxicity [53]. In Type II pyrethroids,
alpha-cyano carbon with the S-configuration presents greater neurotoxicity to
mammals than its epimer [15].
In mammals, the main route of detoxification of trans-isomers is through hydrolysis, while the major metabolic process of cis-isomers is oxidation [67]. In relation
to the acid group, ester hydrolysis greatly depends on the spatial configuration of C-1
and C-3 chiral carbons, with 1R-trans and 1S-trans enantiomers undergoing high
metabolization rates compared to 1R-cis and 1S-cis enantiomers. In the alcohol
portion of the molecule, hydrolysis of esters of primary alcohols (Type I pyrethroids)
is faster than esters of secondary alcohols (Type II pyrethroids) [68]. Hepatic
enzymes, such as carboxylesterases, are important in pyrethroid metabolism. Selective metabolization of trans-permethrin through human pyrethroid-hydrolysing
carboxylesterases (hCE-1 and hCE-2) was observed compared to the hydrolysis
rate of cis-permethrin [31].
In humans, permethrin oxidation occurs through metabolization by cytochrome
P450 enzymes (CYP450) and by alcohol and aldehyde dehydrogenases [69]. The
main metabolites from hydrolysis and oxidation reactions are cis-trans-3-(2,2
dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis-trans-DCCA),
3-phenoxybenzyl alcohol (3-PBAlc), 3-phenoxybenzyl aldehyde (3-PBAld) and
3-phenoxybenzoic acid (3-PBA) [66, 69].
Pyrethroids have been associated with a wide range of toxicological effects upon
the reproductive function of mammals [70–72]. In assays with adult male mice
exposed by oral administration to permethrin, only the cis-isomers resulted in wide
reproductive adverse effects with reduction of epididymal sperm count, sperm
motility and testosterone levels in testes [73]. On the other hand, no adverse effects
on reproductive function were observed after trans-permethrin administration. In
addition, the presence of the urinary metabolite 3-PBA in trans-permethrin treatment
was up to sevenfold higher compared to a treatment by its isomeric pairs
(cis-isomers). Additionally, the hepatic microsomal hydrolase activity for the
162
C. E. T. Parente et al.