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Tricresyl Phosphate (TCP)

Tricresyl phosphate (TCP), is a mixture of three isomeric organophosphate compounds most notably used as a fire retardant and in manufacturing for lacquers and varnishes as a plasticizer. It is a colorless, viscous liquid, although commercial samples are typically yellow. It is virtually insoluble in water, but easily soluble in organic solvents like toluene, hexane, and diethylether among others. It was synthesized by Alexander Williamson in 1854 upon reacting phosphorus pentachloride with cresol (a mixture of para-, ortho-, and meta- isomers of methylphenol), though today's manufacturers can prepare TCP by mixing cresol with phosphorus oxychloride or phosphoric acid as well.

Major Tricresyl Phosphate Applications

Category	Uses
Plasticizer	Vinyl plastics manufacture, solvent for nitrocellulose, in cellulosic molding compositions and used as a flame retardant in rubbers, plastics, and flexible PVC. Typical applications are vinyl tarpaulins, mine conveyer belts, air ducts, cable insulation, and vinyl films.
Lubricant	Additive to extreme pressure lubricants.
Industrial Fluid	Used as a heat exchange medium, antiwear, and non-flammable fluid additive for hydraulic systems, lead scavenger in gasoline for tetraethyllead.

Though otherwise useful, it was the source of a 1977 epidemic of acute polyneuropathy in Sri Lanka where 20 Tamil girls were poisoned by TCP-contaminated gingili oil. It is a toxic substance that causes neuropathy, paralysis in the hands and feet, and/or death for humans and animals alike. It can be ingested, inhaled, or even absorbed through the skin. Its ortho-isomer is notoriously known as a source of several delayed neurotoxic outbreaks across recent history. Contemporary commercial products typically only contain the para- and meta- isomers of TCP due to the lack of neurotoxic potential within these isomers.

To handle or store TCP, specific training must be administered due to its reactivity with commonly used laboratory reagents:

• TCP cannot be used with reducing agents (lithium, aluminum, sodium, and their hydrides) for their reaction creates Phosphine gas. This vapor is toxic and extremely flammable.
• TCP cannot be used with any and all oxidizing agents (perchlorates, peroxides, permanganates, chlorates, among others).

Tri-o-cresyl Phosphate (TOCP)

History

The earliest known mass poisoning event by TOCP started as early as 1899 when six French hospital patients were given a phosphocresote cough mixture containing the organophosphate compound. Pharmacist Jules Brissonet had synthesized this compound in the hopes of treating pulmonary phthisis (tuberculosis), but soon after administration all 6 patients developed polyneuropathy. The original paper ads described this phosphocresote to be:

A bland, limpid liquid, nearly tasteless and odourless, which is not irritating to the gastric mucous membranes. When creosote is combined with phosphoric acid the metabolic action produced is much more marked, and Phosote can be tolerated in larger doses and for a longer continuance than Creosote or Guaiacol. Dose of the preparation, one to two grammes three times a day.

After this, the greatest mass poisoning episode regarding TOCP occurred in 1930 with the introduced of the popular drink "Ginger Jake" (or Jamaica "Jake") during the United States Prohibition era. Though the drink was a primary substitute for alcohol during this period where all alcoholic drinks had been outlawed by the United States Government, it was also listed as a cure for "assorted ailments" in the U.S Pharmocopoeia and thus easy to acquire. An estimate of up to 100,000 people were poisoned and 5,000 paralyzed when a manufacturer of Ginger Jake added Lindol - a compound that consisted mainly of TOCP - to their product. The exact reason for why TOCP was found in Ginger Jake is disputed; some sources claim it was to further extract the Jamaica root, others to water the drink down, and another as a result of contamination from lubricating oils. Regardless of the motive, binges of Ginger Jake from 1930 and onward resulted in what was known to be a "Jake walk," in which patients experienced a highly irregular gait caused by numbness in the legs that followed with eventual paralysis of the wrists and feet. In medical journals it was described to have produced an organophosphate-induced delayed neuropathy (OPIDN) neurodegenerative syndrome, "characterized by distal axonal lesions, ataxia, and neuronal degeneration in the spinal cord and peripheral nervous systems."

The Chemical Structure of Apiol

Parsley Leaves

Mass outbreaks of TOCP were typically characterized by accidental contamination. In 1932, 60 European women experienced TOCP poisoning by means of the abortion-inducing (abortifacient) drug Apiol. This drug, formed by the phenylpropanoid compound extracted from parsley leaves, was exploited throughout history - and even recommended by Hippocrates himself - to terminate pregnancies. The contamination of the modern drug in 1932 was not accidental, but rather included as an "additional stimulus." Those who took the pill experienced comas, convulsions, paralysis of the lower body (paraplegia) and often death Apiol was subsequently criticized by doctors, journalists, and activists alike until its discontinuation, citing that the dangers were too great and the number of poisonings were likely higher than accounted for.

As the years progressed, several other mass poisonings occurred:

• 60 South Africans were poisoned after using contaminated cooking oil that had been stored in drums that previously stored lubricating oil in 1937.
• 80 men within a unit of the Swiss army experienced a similar outbreak when their cooking oil had been contaminated with machine gun oil in 1940.
• 3 English men were poisoned by means of TOCP vaporization when working on a tank in a poorly ventilated area.
• 11 South Africans used water from drums from a paint factory that previously stored TOCP in the 1950s.
• 10,000 people in Morocco were poisoned when they consumed cooking oil contaminated with jet-plane lubricating oil in 1959.

Since then, TOCP has evolved to be used primarily in manufacturing and industrial processes as part of an isomeric mixture generally referred to as TCP. The ortho-isomer is rarely used on its own due to its extremely toxic nature outside of laboratory studies that require isomeric purity, and is generally excluded from commercial products where TCP is involved.

Research

Laboratory

Despite TOCP being known as a weakly anticholinergic compound, a study with topical/systemic administration on slow lorises (Nyticebus coucang coucang) gave rise to the idea that effects may differ between species. Over the course of the project, histochemical studies showed that there was a noticeable reduction in acetylcholinesterase levels and complete absence of cholinesterase in sensory nerve terminations. In addition to this, after examining taste buds there was evidence of degenerating mitochondria, vacuolization, swollen endoplasmic reticulum, cytosegregome and vesicle formation. Degeneration in sensory end-organs and distal nerve fibers were also ultimately observed. The significance of these findings is not clear, but they do allude to the potential that TOCP exposure has even on a cellular level.

In a published study on the effects of TOCP on the mammalian placenta, researchers found that TOCP exposure lead to a significant reduction in the "numbers of implanted embryo, caused atrophy and collapse of the ectoplacental cone, and decreased total areas of placenta and numbers of PCNA-positive cells" due to placental apoptosis, authophagy, and oxidative stress In contrast to the control groups where no TOCP was administered, the expression of the genes that encoded for placental development in adult female Kunming mice were severely downregulated when they were treated with TOCP. It induced placental apoptosis and autophagy - the placental death and reabsorption/consumption of its tissues by the body - by "upregulating P53, Bax, Beclin-1, ratio of LC3II/LC3 I and Atg5," and downregulating the Bcl-2 protein." An important and notable observation in conjunction with the up/downregulation of placental development proteins was that TOCP exposure increased the production of hydrogen peroxide (H₂O₂) and malondialdehyde, a highly reactive marker of oxidative stress.

Toxicity

Biochemical Pathways

Though TOCP has been noted to be excreted through urine and feces, its presence in the body along with its metabolites still causes significant damage. It's absorption in the body has been simulated in cat studies where it was noted that the highest concentration of TOCP was found in the liver, gall bladder, kidneys, and along the nerves that lead down the legs and buttocks (sciatic nerve). It can be metabolized in three steps, whereupon ingestion it is aided by the hepatic cytochrome P450 system:

1. Hydroxylation at one or more methyl groups
2. Dearylation at one of the o-cresyl groups
3. Oxidation at the hydroxymethyl groups to an aldehyde or a carboxylic acid.

The first step results in a saligenin cyclic o-tolyl phosphate (SCOTP) intermediate, a dangerously neurotoxic ester to any organism. To the right, the first step of TOCP metabolism is depicted by means of chemical structures. This intermediate is able to inhibit neuropathy target esterase (NTE) and results in the classic organophosphate-induced delayed neuropathy (OPIDN). In tandem, TOCP exerts physical damage by causing axonal destruction and myelin disintegration within specialized cells that transmit nerve impulses (neurons).

In addition to the formation of SCOTP, the interactions between TOCP and two different human cytochrome P450 complexes (1A2 and 3A4) can further produce 2-(ortho-cresyl)-4H-1,2,3-benzodioxaphosphoran-2-one (CBDP). This metabolite can bind to butyrylcholinesterase (BuChE) and/or acetylcholinesterase (AChE).

Binding to BuChE results in no adverse effects, for its typical role is to covalently bind to organophosphate poisons and detoxify them by inactivation. The dangers in metabolizing TOCP to CBDP occur when its potential to bind to AChE become imminent, for inactivation of the enzyme in nerve synapses can be lethal. The enzyme plays a tantamount role in terminating nerve impulse transmission "by hydrolyzing the neurotransmitter acetylcholine." Upon inactivation, acetylcholine can no longer be broken down in the body and results in uncontrollable muscle spasms, paralyzed breathing (bradycardia), convulsions, and/or death. Luckily, TOCP is considered a weak AChE inhibitor.

Onset & Treatment

In humans, the first symptoms are weakness/paralysis of the hands and feet on both sides of the body due to damage to the peripheral nervous system (polyneuropathy) and a sensation of pins-and-needles (paraesthesia). Onset typically occurs beween 3-28 days from initial exposure. If ingested, this can be preceded by gastrointestinal symptoms that include nausea, vomiting, and diarrhea. Rates of metabolism vary by species and by individual; some people developed severe polyneuropathy after ingesting 0.15g of TOCP, whereas others have been reported asymptomatic after 1-2g. Though death is uncommon in acute exposure cases, the result of paralysis can last for months or years due to differences in gender, age, and route of exposure. The cardinal treatment is physical therapy to restore the use of the hands and feet, though it can take up to 4 years to only regain a fraction of motor control.

Exposure to TOCP has been characterized by a list of observations:

• Cholinesterase levels will remain unchanged or show no significant changes.
• Electromyography will show partial or complete reactions of degeneration.
• An increase of protein in cerebrospinal fluid.
• Swelling of the parotid glands (non-tender).

Tri-p-cresyl Phosphate (TPCP)

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Tri-m-cresyl Phosphate (TMCP)

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