Piperonyl butoxide is a synergist used in a wide variety of pesticides (Tozzi A 1998). Synergists are chemicals that lack pesticidal effects of their own but enhance the pesticidal properties of other chemicals.
Piperonyl butoxide (PBO), suppresses the activity of cytochrome P-450 monooxygenases, and S,S,S-tributyl phosphorotrithioate (DEF) (Ninsin KD et al 2005). Cytochrome P-450 monooxygenases have many functions, including breakdown of toxic chemicals and transformation of hormones. S,S,S-tributyl phosphorotrithioate (DEF) is an inhibitor of esterases.
Piperonyl butoxide is added to pesticides containing chemicals like pyrethrins (bio-allethrin), pyrethroids (permethrin), rotenone, and carbamates.
Piperonyl butoxide is not only used as a pesticide synergist it is used as a food additive!!! too (Suzuki H. 1995).
Symptoms caused by ingestion of PBO in large doses, include nausea, cramps, vomiting, and diarrhea (Prentiss, Inc. 1998).
Inhalation of large amounts of PBO may cause tearing, salivation, labored breathing (WHO and FAO Evaluations 1995 Pp. 282), accumulation of fluids in the lungs (Bateman, D.N 2000), and may be linked to respiratory problems, including asthma.
Acute and repeated dermal (skin) and eye contact has been shown to be slightly irritating, but is not linked to long-term damage (Breathnach R. 1998).
Chemistry
Researchers developed piperonyl butoxide in 1947 using naturally-occurring safrole as a key raw material (Tozzi A. 1998, Knowles C. O. 1991).
Safrole is a natural constituent of a number of spices such as nutmeg, mace, cinnamon,
anise, black pepper and sweet basil. The most important dietary sources are nutmeg,
mace and their essential oils. Safrole is also present in cola drinks
(Council of Europe, 1997)!
Researchers at the UFR de Pharmacie (France), found safrole in all of the PBO samples they tested (Schreiber-Deturmeny, E.M et al 1993).
In 1997 the Committee of Experts on Flavouring Substances (CEFS) of the Council of Europe evaluated safrole: “Safrole is a weak hepatocarcinogen in experimental animal studies but is also a genotoxic and a transplacental carcinogen. Efforts should be made to reduce its consumption by foods and beverages as far as possible”.
The National Toxicology Program classifies safrole as: “reasonably anticipated to be a human carcinogen.” (U.S. Department of Health and Human Services, 9th report on carcinogens 2001). Safrole causes in vitro ‘sister chromatid exchanges’ (Tayama, S. 1996).
Research
DNA damage
PBO induced mutagenicity in cultured human RSa cells and caused mutations in gene OuaR. PBO also caused mutations in K-ras, a gene believed to be involved in neoplastic (tumorous) changes (Suzuki H et al 1995). PBO causes sister chromatid exchanges in cultures of
cells from hamster ovaries (Tayama, S. 1996).
Cancer
The carcinogenicity of PBO was in 1995 still controversial to some reviewers. In a 1995 review, the World Health Organization, identified five other studies that found no evidence that PBO exposure caused cancer (WHO and FAO Evaluations 1995 pp 288-293). At this moment much more studies do suggest the carcinogenic effect… .
Since 1995, EPA has classified piperonyl butoxide as carcinogen (a chemical that causes cancer). EPA’s classification of piperonyl butoxide is ‘Group C’, a possible human carcinogen (U.S. EPA 1995). A study conducted by PBO manufacturers found the incidence of lymph and thyroid tumours increased with increasing exposure to PBO (WHO and FAO Evaluations 1995 Pp. 291).
By now it is reasonable to call PBO a liver carcinogen (U.S. EPA. Office of Prevention, Pesticides and Toxic Substances. (1995), and below mentioned references).
In addition, PBO can increase the carcinogenicity of other cancer-causing chemicals. Researchers found that the combination of Freon (a refrigerant that was also used as a propellant in aerosol pesticides) and PBO was more carcinogenic than either chemical alone (Epstein SS et al 1967). The liver carcinogen N-hydroxy-2-acetylaminofluorene together with PBO is also more carcinogenic than than either chemical alone (Fujii, K et al 1979).
Reproduction
Atrophy of the testes was observed in a two-year feeding study with rats (U.S. EPA. 1988. R12-13), along with some decreases in weight of the seminal vesicles (sperm-producing
structures) (Breathnach, R. 1998).
Pregnant mice were given a single dose of PBO on the ninth day of their pregnancy. The weight of fetuses from exposed mothers was less than the weight of fetuses from unexposed mothers. The number
of fetal deaths was also higher for exposed mothers. These researchers also found that the frequency of fetuses with defective or missing fingers was higher for mothers exposed at all, but the lowest dose level (Tanaka T et al 1994).
A study found that the incidence of a bone defect was higher in the offspring of rats exposed during
pregnancy than in the offspring of unexposed rats. The incidence was dose-related and was 2 to 4 times
higher for exposed rats than for unexposed ones. However, EPA concurred “with the study author’s conclusions that these effects were not related to treatment” (U.S. EPA. Office of Prevention, Pesticides and Toxic Substances 1993)?!
The offspring of mice that were fed PBO before, during, and after pregnancy weighted less than the offspring of unexposed mice. This decrease occurred at all the dose levels tested.
In addition, PBO caused changes in the home recognition olfactory behaviour of the offspring of exposed mothers. In a test where the mice had a choice of entering a compartment with wood chips from their home cage or entering a compartment with fresh (unused) chips, the offspring of exposed mothers were less likely to enter the compartment that smelled like home, than the offspring of unexposed mothers.
This behavioural change occurred at all, but the lowest dose level tested (Tanaka T 1992; Tanaka T 2003).
In the third generation, several behaviours, including the olfactory home-recognition behaviour mentioned above, were also affected by PBO exposure. The effects on the weight of nursing pups occurred at all dose levels tested, the behavioral effects occurred at all, but the lowest dose level (Tanaka T et al 1992).
Behaviour, brain
See at the item ‘Reproduction’ too.
PBO reduced significantly ambulation and rearing (Tanaka, T 1993)
PBO also reduces cholinesterase. This enzyme plays a role in transmitting nerve impulses from one nerve cell to another or to muscle cells (Ware, G.W 2000);
PBO can increase the neurotoxicity of methylmercury, a neurotoxin (Friedman, M.A et al 1978), and of bioallethrin and of permethrin. In 2005 Grosman N et al demonstrated that PBO inhibits the ATPase activity of brain synaptosomes and peritoneal leukocyte membranes. S-bioallethrin (esbiol) potentiates the inhibition.
Immune system
The first time medical researchers documented PBO’s ability to inhibit normal functions of the immune system was in 1979: PBO inhibited the immune response of lymphocytes, and PBO was a stronger inhibitor (25%) than the seven other pesticide chemicals tested (Lee T -P et al 1979).
Mitsumori K et al suspected in 1996 food shortage to be due to the lymfo-hematopatic changes, but in 1999 Diel et al found similar results: PBO also caused about a 50% inhibition of human T-lymphocyte proliferation and together with S-bioallethrin the inhibiting was even more effective.
The ATPase activity of leukocyte membranes tends to be more susceptible to inhibition, than inhibition of brain synaptosomes. But with esbiol (bioallethrin) a true potentiation takes place (Grosman N et al 2005).
Organs
LARYNX
Breathing Piperonyl butoxide damages the larynx, there was metaplasia, transformation of cells to an atypical form, and hyperplasia, an abnormal increase in the number of cells (U.S. EPA 1994).
LIVER
A lot of research does support PBO's harm to the liver (rats, mice, dogs) and increased levels of cholesterol are common (amongst others Fujitani, T et al 1993 and WHO and FAO 1996 p. 287-288). Liver damage occurred after less then one week of exposure (Fujitani T, et al 1993).
A broad range of cell degenerations was obvious on cellular level. Including celnecroses, vacuoles in hepatocyts (Fujitani T, et al 1993). PBO finaly induces liver cancer (rats, mice) (Friedman MA. 1979, Takahashi O et al 1994 a, Takahashi O et al 1994 b, Takahashi O et al 1997, Okamiya H et al 1998, Muguruma M, et al 2007). This as a result of oxidative stress, the formation of ROS (Reactive oxygen species) products and DNA damage (Muguruma M, et al 2006, Muguruma M, et al 2007).
Fujitani T et al (1993) did find bile duct hyperplasia.
BLOOD
Increased levels of cholesterol are common (U.S. EPA. 1988 Reg. No.: 4816- 72). At the highest dose, a three-month exposure to PBO, increased the blood levels of cholesterol in rats about double the level in unexposed rats (Fujitani T et al 1992).
BPO induces hemorrhages in the stomach and cecum, and anaemia, and trombocytaemie (Takahashi O et al 1994, Takahashi O et al feb. 1994).
KIDNEYS
The kidney of treated rats showed atrophy of the epithelium in the proximal convoluted tubules (Fujitani, T et al 1992). Relative kidney weights and serum urea nitrogen levels were increased, atrophy of the proximal tubules, dilation of tubules, cell infiltration, fibrosis and accumulation of yellow-brown pigment in the proximal tubular cells were seen (Fujitani, T et al 1992). Takahashi O et al (1994) state: Nephrotoxicity were also observed related to exposure.
LUNGS
BPO causes degenerative lesions of long alveoli (Takahashi O et al 1994).
Hormones and glands
Piperonyl butoxide’s effect on Cytochrome P450 enzymes is biphasic;
It both inhibits and induces enzymatic activity. The inhibition of Cytochrome P450 enzymes occurs rapidly, followed by a slow induction process. The rapid inhibition of Cytochrome P450 enzymes contributes to piperonyl butoxide’s effectiveness as a synergist. P450 enzymes break steroids (a class of chemicals that includes many sex hormones) down (Hodgson, E et al 1998).
So it is not surprising that PBO can have some hormonal effects.
A study showed that long-term exposure of rats to PBO, damages hormone-related organs. In exposed animals, thyroid glands were larger than in unexposed animals. Also, adrenal glands in exposed females
were larger than in unexposed females, and pituitary glands were smaller in exposed males (WHO and FAO Evaluations 1995 pp 290-291).
