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14.3.2.3.1. Piperonyl butoxide Piperonyl butoxide has negligible acute toxicity, and WHO has classified it as unlikely to
present an acute hazard in normal use. Both short-term and long-term studies, however, show that it is responsible for hepatic toxicity, which is characterized by liver enlarge-
ment with associated hypertrophic hepatocytes, focal necrosis and at times alteration of some clinical chemical parameters. Piperonyl butoxide was shown to be carcinogenic at
doses toxic to the liver, and it caused general toxicity. Also, piperonyl butoxide was not shown to be genotoxic, and therefore JMPR did not consider the cocarcinogenic effect
observed in animals to be relevant to people WHO IPCS, 2002. These effects were considered to be secondary to the ability of piperonyl butoxide to induce hepatic cyto-
chrome P450 enzymes, a large group of monooxygenase enzymes responsible for the metabolism of toxic hydrocarbons. Moreover, piperonyl butoxide was not embryotoxic or
teratogenic in rats or rabbits. Furthermore, it was a mild dermal and ocular irritant, but not a dermal sensitizer, in rabbits.
Some experiments with piperonyl butoxide have been performed on people. A study reported by JMPR WHO IPCS, 2002, in which a formulation containing 3 piperonyl
butoxide was spread onto the ventral forearm of adult male volunteers, indicated that about 8 of the applied dose was absorbed through the skin. The percutaneous absorp-
tion of pyrethrins and piperonyl butoxide from the scalp was calculated to be 7.5 of the applied dose for pyrethrins and 8.3 for piperonyl butoxide. With a 7-day urinary col-
lection, 1.9± 1.2 standard deviation of the dose of pyrethrins and 2.1± 0.6 of the dose of piperonyl butoxide applied, were absorbed through the forearm skin. An hour after
application, blood samples contained no detectable radioactivity Wester, Bucks Maibach, 1994. The ADI was 0–0.02mgkg BW per day, but an ARfD value was not
established.
14.3.2.4. Anticoagulant rodenticides
Anticoagulants used as rodenticides are antimetabolites of vitamin K and inhibit the syn- thesis of prothrombin Ecobichon, 1996. Warfarin was the first compound to be intro-
duced and is the prototypical short-acting rodenticide. Due to the emergence of warfa- rin-resistant rats, so-called superwarfarins or long-acting anticoagulants were developed.
These include diphacinone, brodifacoum, bromadiolone and chlorophacinone. They dif- fer from warfarin in a number of respects: a longer polycyclic hydrocarbon side chain,
higher lipid solubility, accumulation in the liver, higher potency on a molar basis and prolonged action. Accidental or intentional exposure to either type of anticoagulant cau-
sed prolonged clotting failure coagulopathy and, in severe cases, death. Short-acting anticoagulants have caused death at an estimated dose of 50mgkg per day for 8 days
Lange Terveer, 1954.
In people, accidental percutaneous exposure to talcum powder contaminated with 1.7–6.5 warfarin caused toxicity and death in Vietnamese infants Martin-Bouyer et al.,
1983. In adults, a single oral dose of 1mgkg is considered to cause therapeutic pro- thrombin values. Less information is available for superwarfarins, which are expected to
cause longer-lasting coagulation defects. Data collected from poison control centres indi- cate that a single acute unintentional rodenticide anticoagulant ingestion rarely causes
Pesticides: risks and hazards
492
potency and low mammalian toxicity. The latter quality is reflected in ratios of rat LD
50
to insect LD
50
being generally higher than 1000, whereas for other pesticides they are in the range 1–50 Elliot, 1976.
Acute poisoning from pyrethroids is characterized by dizziness, headache, nausea, mus- cular fasciculation, convulsive attacks and coma He et al., 1989; Chen et al., 1991. Two
patterns of symptoms are described in rats after acute intoxication, depending on the pre- sence or the absence of an αcyano-group substituent: the so-called T-syndrome aggres-
sive sparring, sensitivity to external stimuli and tremors and the so-called CS-syndrome choreathetosis a disorder that causes involuntary movement or spasms, salivation and
seizures, respectively. Sometimes, however, the two syndromes may combine to give a more complex one Aldridge, 1990. Cases of acute pyrethroid poisoning in China have
been reviewed, but it was not possible to differentiate the two syndromes in people He et al., 1988.
Occupational exposures often result in abnormal skin sensations – mainly of the face – described as burning and tingling He et al., 1989; Chen et al., 1991; Moretto, 1991; Zhang
et al., 1991. Symptoms appear shortly after beginning work and disappear within 24 hours. Most pyrethroids cause these sensations, with the following order of decreasing
potency: deltamethrin, flucythrinate, cypermethrin = fenvalerate, permethrin Aldridge, 1990. This neurotoxicity is due to a local effect, since only unprotected parts of the skin
are affected. Pyrethroids are known to act on sodium channels, thereby causing repeti- tive firing of the sensory nerve endings of the skin Aldridge, 1990. However, electro-
physiological studies performed on the arms and legs of exposed subjects that complai- ned of cutaneous sensations were negative Le Quesne, Maxwell Butterworth, 1981.
Neonatal rats are known to be 4–17 times more vulnerable to acutely toxic doses of pyre- throids than adults. This probably can be attributed wholly to their smaller capacity for
metabolic detoxification. In contrast, there is no evidence that shows them to be more susceptible to low doses that cause no toxic effects in adults Ray, 2001. In several studies
performed in one laboratory, the pyrethroids permethrin and deltamethrin were repor- ted to induce changes in behaviour and in some neurochemical parameters in adult mice
that were administered the pyrethroids, during their neonatal life, at doses not causing overt toxicity. However, others did not duplicate these findings, and the findings are not
consistent with the results of several multigeneration, regulatory studies Ray, 2001.
ADIs for pyrethroids vary between 0–0.07mgkg BW per day and 0–0.002mgkg BW per day, depending on the AI considered ARfDs are roughly an order of magnitude
higher.
14.3.2.3. Insecticide synergists
Insecticide synergists are chemicals that enhance the insecticidal activity of other chemi- cals, such as pyrethrins and synthetic pyrethroids. These synergists are mixed with insec-
ticides in end-use product formulations. They are not used alone. These compounds have very low or negligible levels of toxicity. Piperonyl butoxide is the most commonly used
insecticide synergist.
Public Health Significance of Urban Pests
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changes in plasma lipid concentrations, particularly cholesterol, at doses of 120 mgkg BW per day and above in rats. Also, some evidence showed that the compound might
cause modest anaemia in mice, rats and dogs at high doses. In long-term studies of toxi- city in mice, pyriproxyfen also caused a dose-dependent increase in the occurrence of sys-
temic amyloidosis, which was associated with increased mortality rates at doses greater than 16 mgkg BW per day. Pyriproxyfen was not carcinogenic in mice or rats WHO
IPCS, 2002, and it showed no evidence of carcinogenicity in a one-year study in dogs at doses up to 1000 mgkg BW per day. Pyriproxyfen was not genotoxic in a range of tests
for mutagenicity and cytogenicity in vitro and in vivo. Moreover, it caused little deve- lopmental toxicity and was not teratogenic. The ADI was 0–0.1mgkg BW per day; and
no ARfD value has been established.
14.3.2.6. N eonicotinoid insecticides
These insecticides have very low toxicity in mammals and, being of relatively recent introduction, have a very small, if any, record of human poisoning or excessive exposure.
14.3.2.6.1. Imidachloprid JMPR reports that a 4-year-old child who ingested about 10mgkg BW of a veterinary
preparation of imidacloprid showed no signs of poisoning or adverse health effects. In two fatal cases with this compound, blood concentrations were 12.5µgml and 2.05µgml
Proenca et al., 2005. In a case of acute ingestion of a formulation containing 9.7 imi- dacloprid 2 surfactant and the balance as solvent N-methyl pyrrolidone, clinical
manifestations included drowsiness, disorientation, dizziness, oral and gastroesophageal erosions, haemorrhagic gastritis, productive cough, fever, leukocytosis and hyperglycae-
mia. The patient recovered without complication with supportive treatment, was dis- charged four days after ingestion, and the follow-up barium upper gastrointestinal exa-
mination a month later was normal. Because a moderate to high dose of imidacloprid in animals causes central nervous system activation similar to nicotine, including tremors,
impaired pupillary function and hypothermia, it is unclear whether imidacloprid had a causal role in the patient’s initial drowsiness and dizziness. It is more likely that the for-
mulation ingredients, particularly N-methyl pyrrolidone, caused most of the clinical symptoms, including minor central nervous system depression, gastrointestinal irritation
and hyperglycaemia Wu, Lin Gheng, 2001. As reported by JMPR, periodic exami- nations of employees exposed to imidacloprid showed no adverse health effects.
Imidacloprid is moderately toxic to rats oral LD
50
: 380–650mgkg BW and mice oral LD
50
: 130–170mgkg BW. Behavioural and respiratory signs, disturbances of motility, narrowed palpebral fissures, transient trembling and spasms were seen in rats and mice
treated orally at doses greater than or equal to 200mgkg BW and greater than or equal to 71mgkg BW, respectively. The clinical signs were reversed within six days. The LC
50
for acute exposure to an aerosol could not be determined exactly, as rats tolerated inha- lation for four hours of the maximum concentration of dust that could be produced tech-
nically 0.069mgl of air without signs or deaths.
Imidacloprid did not irritate the skin or eyes of rabbits and did not sensitize the skin of guinea-pigs in a maximization test. A reduced gain in BW was the most sensitive toxi-
Pesticides: risks and hazards
494
laboratory or clinical evidence of excessive anticoagulation Wedin Benson, 2000. Therefore, although the number of cases of accidental ingestion is relatively high, the
outcome is generally without consequences.
It is known that warfarin anticoagulation therapy during the first trimester of gestation may cause developmental disorders in embryos such as nasal cartilage hypoplasia and
skeletal abnormalities, whereas in the late third trimester it may result in prenatal, per- inatal or postnatal haemorrhages. Ocular and neurological abnormalities have also been
observed after warfarin treatment during pregnancy. Known adverse effects that occur during anticoagulant treatment, such as cutaneous and subcutaneous tissue necrosis, pur-
ple toes syndrome and dermatitis medicamentosa, do not occur after massive accidental exposure or after prolonged environmental exposure. The laboratory parameter to be
assessed after anticoagulant ingestion is PTPTT prothrombinpartial thromboplastin time or INR international normalized ratio, to be measured 24–48 hours after poiso-
ning. No ADI or ARfD values have been established.
14.3.2.5. IGRs
