55: Pharmaceutical Additives

During the last century there were several outbreaks of toxicity in the United States associated with pharmaceutical additives (Chap. 2). The 1937 Massengill sulfanilamide disaster is the most notorious of these epidemics. Diethylene glycol, an excellent solvent and potent nephrotoxin, was substituted for the additives propylene glycol and glycerin in the liquid formulation of a new sulfanilamide antibiotic because of lower cost.^25,62,69 As a result, more than 100 people died from acute kidney failure.²⁵ Outbreaks of acute kidney failure occurred when diethylene glycol was used to solubilize acetaminophen in South Africa, Bangladesh, Nigeria, and Haiti, cough syrup in Panama, and teething powder in Nigera.^{20,28,30,71,81,122,133}

In December 1983, a new parenteral vitamin E formulation (E-Ferol) was introduced. It contained 25 units/mL of α-tocopherol acetate, 9% polysorbate 80, 1% polysorbate 20, and water for injection. At the time, no premarketing testing was required for new formulations of an already approved drug. Several months after its release, a fatal syndrome in low-birth-weight infants, characterized by thrombocytopenia, acute kidney injury, cholestasis, hepatomegaly, and ascites, was described.^1,109 Thirty-eight deaths and 43 cases of severe symptoms were attributed to E-Ferol. Vitamin E was thought to be the cause and E-Ferol was recalled from the market 4 months after its release. It is now believed that the polysorbate emulsifiers were responsible.¹

Although these additive-related occurrences are rare, relative to the frequency of pharmaceutical additive use, they illustrate the potential of pharmaceutical additive toxicity.

Pharmaceuticals are labeled specifically to focus attention on the active ingredient(s) of a product, thus giving the misimpression that additive ingredients are inert and unimportant. Additives, or excipients as they are more properly termed, are necessary to act as vehicles, add color, improve taste, provide consistency, enhance stability and solubility, and impart antimicrobial properties to medicinal formulations. Although it is true that most cases of excipient toxicity involve exposure to large quantities, or to prolonged or improper use, these adverse events are nonetheless related to the toxicologic properties of the excipient.

Prior to selecting the specific additives and quantity necessary for a drug formulation, the drug manufacturer must consider several factors, including the active ingredient’s physical form, its solubility and stability, the desired final dosage form and route of administration, and compatibility with the dispensing container materials. The same active ingredient may require different excipients to impart appropriate pharmacokinetic characteristics to different dosage forms, such as in long-acting and immediate-release formulations. Similarly, multiple-dose injection vials containing the same active ingredients as single dose vials specifically require the addition of a bacteriostatic xenobiotic not necessary for single dose vials.

Unlike requirements for active ingredients, there is no specific US Food and Drug Administration (FDA) approval system for pharmaceutical excipients. As such, the FDA determines the amount and type of data necessary to support the use of a specific excipient on a case by case basis. Under current practice, only excipients that were previously permitted for use in foods or pharmaceuticals are defined as generally recognized as safe (GRAS), or “GRAS listed.” All components of a pharmaceutical product, including excipients, must be produced in accordance with current good manufacturing practice standards to ensure purity. The Safety Committee of the International Pharmaceutical Excipients Council developed guidelines for the toxicologic testing of new excipients.¹⁶¹ Because of patent protection laws, it was not until very recently that manufacturers were required to provide a list of inactive ingredients contained in all pharmaceutical products. Although it is becoming easier to identify pharmaceutical additives in products, information on their effects and the mechanisms by which they cause adverse responses are often unknown or difficult to obtain.

This chapter summarizes the available literature on commonly used additives associated with direct toxicities (Table 55–1). Data on pharmacokinetics and mechanism of toxicity are presented where data are available. Although many additives are associated with hypersensitivity reactions, including anaphylaxis, these are not discussed because of their nonpharmacologic basis. However, excipients should always be considered as possibly causative in patients who develop hypersensitivity reactions.

Benzalkonium chloride (BAC, BAK), or alkyldimethyl (phenylmethyl) ammonium chloride, is a quaternary ammonium cationic surfactant composed of a mixture of alkyl benzyl dimethyl ammonium chlorides. Although it is the most widely used ophthalmic preservative in the United States, it is also considered the most cytotoxic (Table 55–2).^87,94 Benzalkonium chloride is also used in otic and nasal formulations, and in some small-volume parenteral preparations. The antimicrobial activity of BAC includes Gram-positive and Gram-negative bacteria, and some viruses, fungi, and protozoa. Because of its rapid onset of action, good tissue penetration, and long duration of action, BAC is preferred over other preservatives. The concentration of BAC in ophthalmic medications usually ranges from 0.004% to 0.01%.⁹⁴ Strong BAC solutions (> 0.1%) can be caustic (Chap. 106).

Ophthalmic Toxicity

Corneal epithelial cells harvested from human cadavers within 12 hours of death were exposed to a medium containing 0.01% BAC.¹⁵⁸ The surfactant properties of BAC resulted in intracellular matrix dissolution and loss of epithelial superficial layers. Following exposure to the medium, mitotic activity ceased and degenerative changes to corneal epithelium were noted. During a 24-hour observation period, epithelial cell cytokinetic or mitotic activity did not occur. Patients with compromised corneal epithelia may be at increased risk for the adverse effects of BAC.¹⁵⁸

Two case reports demonstrate the potential toxicity of BAC and highlight the difficulty of diagnosing BAC toxicity. A 36 year-old woman complained of decreased vision when she inadvertently switched from Lensrins, a contact lens cleaning solution, to Dacriose, an isotonic boric acid solution preserved with BAC. After 3 days, she had inflammation, pain, and decreased visual acuity. Examination of the cornea revealed many superficial punctate erosions of the epithelium. An in vitro experiment identified significant binding of BAC to soft contact lenses.⁵⁷ In the second case, a 56 year-old man diagnosed with keratoconjunctivitis sicca was treated with topical antibiotics and artificial tears containing BAC. Following one year of continual use, the patient developed intractable pain, photophobia, and extensive breakdown of the corneal epithelium. Not suspecting the BAC containing products, the patient continued to use the artificial tears solution for another 9 years despite continued pain and decreasing visual acuity. Replacement with a preservative free saline solution resulted in resolution of pain, photophobia, and corneal changes.⁹⁴ Furthermore, there are newer ophthalmic medication preservatives available (eg, polyquaternium-1, stabilized oxychloride complex, sodium perborate, SofZia), which appear to be less toxic than BAC and may ultimately replace BAC.⁴

A case series of corneal endothelial injury following the inadvertent intraocular use of balanced salt solution (BSS) preserved with BAC instead of preservative free BSS in 12 patients undergoing phacoemulsification, a surgical technique to remove cataract lenses. The BSS, was instilled in the anterior chamber. The operating room had run out of preservative free BSS and, unbeknownst to the surgeon, it was replaced with the BAC containing BSS, which contained 0.013% BAC. This is in excess of recommended concentration for intraocular use and is associated with corneal endothelial injury and edema. Within 48 hours of instillation of the BSS, the visual acuity in all 12 patients was limited to only being able to count fingers at two feet. This persisted in 11 of the patients at a 6 month follow-up evaluation after the instillation of the BSS. One patient did have improvement at 6 months of visual acuity to 20/120 and 20/30 without and with pinholes, respectively.⁹⁶

Nasopharyngeal and Oropharyngeal Toxicity

Human adenoidal tissue was exposed to oxymetazoline nasal spray preserved with BAC at concentrations ranging from 0.005 to 0.15 mg/mL for 1 to 30 minutes.¹⁵ Irregular and broken epithelial cells occurred at all concentrations; however, these findings developed earlier and more frequently with the higher concentrations. The number of beating ciliary bodies also decreased as the duration and the concentrations increased. Benzalkonium chloride may decrease the viscosity of the normal protective mucous lining of the naso- and oropharynx, resulting in cytotoxicity.

Administration of one of three nasal corticosteroid sprays, beclomethasone dipropionate, flunisolide, budesonide, preserved with either 0.031% or 0.022% BAC in the right nostril of rats twice daily for 21 days caused squamous cell metaplasia and a decrease in the number of goblet cells, cilia, and mucus.¹⁶ No histologic changes occurred in rats receiving any of the preservative-free steroids or in tissue exposed to 0.9% sodium chloride solution administered into the left nostril as the control. Similarly, in another study, epithelial desquamation, inflammation, and edema occurred when 0.05% and 0.10% BAC was applied hourly to the nasal cavities of rats for 8 hours.⁹⁰ No lesions developed in the nasal cavities of rats receiving 0.01% BAC.

In an in vitro study, cultured human nasal epithelial cells were exposed to varying concentrations of BAC compared with another preservative, potassium sorbate (PS), with phosphate-buffered saline (PBS) as a control. Cell viability was greatly reduced at the higher concentrations of BAC compared with no decrease in cell viability in the PS or PBS groups. Additionally, at concentrations used clinically loss of microvilli, destruction of cell membranes, and poor cytoskeletal alignment demonstrated by electron microscopy occurred.⁷⁸

An in vitro study of human nasal mucosa exposed mucosa to either fluticasone or mometasone preserved with either BAC or PS at various concentrations with subsequent measure of ciliary beat frequency. While PS did not affect ciliary beat frequency at any concentration, BAC adversely affected ciliary beat frequency. At lower concentrations, BAC slowed ciliary beat frequency and brought it to standstill at higher concentrations.⁷⁹

Benzyl alcohol (benzene methanol) is a colorless, oily liquid with a faint aromatic odor that is most commonly added to pharmaceuticals as a bacteriostatic agent (Table 55–3). In 1982, a “gasping” syndrome, which included hypotension, bradycardia, gasping respirations, hypotonia, progressive metabolic acidosis, seizures, cardiovascular collapse, and death, was first described in low-birth-weight neonates in intensive care units.^21,64,101 All the infants had received either bacteriostatic water or sodium chloride solution containing 0.9% benzyl alcohol to flush intravenous catheters or in parenteral medications reconstituted with bacteriostatic water or saline.^21,64 The syndrome occurred in infants who had received more than 99 mg/kg of benzyl alcohol (range, 99–234 mg/kg).⁶⁴ The World Health Organization (WHO) currently estimates the acceptable daily intake of benzyl alcohol to be not more than 5 mg/kg body weight.²³

Pharmacokinetics

In adults, benzyl alcohol is oxidized to benzoic acid, conjugated in the liver with glycine, and excreted in the urine as hippuric acid. Preterm babies have a greater ability to metabolize benzyl alcohol to benzoic acid than do term babies, but are unable to convert benzoic acid to hippuric acid, possibly because of glycine deficiency. This results in the accumulation of benzoic acid (Fig. 55–1).⁶⁴ A fatal case of metabolic acidosis was reported in a 5 year-old girl who had received 2.4 mg/kg/h diazepam preserved with benzyl alcohol for 36 hours to control status epilepticus. Elevated benzoic acid ­concentrations were identified in serum and urine samples. The estimated daily dosage of benzyl alcohol was 180 mg/kg.^64,97

Neurologic Toxicity

Benzyl alcohol is believed to have a role in the increased frequency of cerebral intraventricular hemorrhages and mortality reported in very-low-­birth weight (VLBW) infants (weight < 1000 g) who received flush solutions preserved with benzyl alcohol.⁷⁷ An increased incidence of developmental delay and cerebral palsy was also noted in the same VLBW patients, suggesting a secondary damaging effect of benzyl alcohol.¹³

There are several case reports of transient paraplegia following the intrathecal or epidural administration of chemotherapeutics or analgesics containing benzyl alcohol as a preservative.^9,39,70,139 The local anesthetic effects are most likely responsible for the immediate paraparesis and limited duration of effects, rather than actual demyelination of nerve roots. In a rat study, lumbosacral dorsal root action potential amplitudes were measured after exposure to 0.9% or 1.5% benzyl alcohol solutions in either 0.9% sodium chloride solution or distilled water.⁷⁰ Rats exposed to all benzyl alcohol ­solutions for less than one minute had inhibited dorsal root action potentials. This was attributed to the local anesthetic effects of benzyl alcohol as function was 50% to 90% restored after rinsing the nerves with 0.9% sodium chloride solution. Chronic intrathecal exposure to benzyl alcohol 0.9% over 7 days resulted in scattered areas of demyelinization and early remyelinization. The 1.5% benzyl alcohol solution–exposed dorsal nerve roots showed greater changes with widespread areas of demyelinization and fatty degeneration of nerve fibers.

Chlorobutanol, or chlorbutol (1,1,1-trichloro-2-methyl-2-propanol), is available as volatile, white crystals with an odor of camphor. Chlorobutanol has antibacterial and antifungal properties and is widely used as a preservative in injectable, ophthalmic, otic, and cosmetic preparations at concentrations up to 0.5% (Table 55–4). Chlorobutanol also has mild sedative and local anesthetic properties and was formerly used therapeutically as a sedative-hypnotic.¹⁹ Because chlorobutanol is a halogenated hydrocarbon, theoretically it can sensitize the myocardium to catecholamines, although no cases of ventricular dysrhythmias are described in the literature to date. The lethal human chlorobutanol dose is estimated to be 50 to 500 mg/kg.¹¹⁷

Central Nervous System Toxicity

Chlorobutanol has a chemical structure similar to trichloroethanol (Fig. 74–1), the active metabolite of chloral hydrate, and is believed to exhibit similar pharmacologic properties. Central nervous system depression was reported in a 40 year-old alcoholic man who chronically abused Seducaps, formerly available in Australia and several other countries, a nonprescription hypnotic containing chlorobutanol as the active ingredient.¹⁹ On admission to the emergency department he had drowsiness, dysarthria, slurred speech, and occasional episodes of myoclonic movements. His peak serum chlorobutanol concentration was 100 µg/mL, decreasing to 48 µg/mL over 2 weeks, with a half-life of 3 days based on serial declining levels. This is similar to human volunteer pharmacokinetic data following oral administration of chlorobutanol demonstrating an elimination half-life of 10.3 ± 1.3 days.¹⁵⁹ His speech abnormality resolved after 4 weeks. Only chlorobutanol was detected in the patient’s urine or serum. In a second case, a possible central nervous system depressant effect from chlorobutanol was suggested in a 19 year-old woman treated with high doses of intravenous morphine preserved with chlorobutanol.⁴⁵ She received approximately 90 mg/h of chlorobutanol for several days. Her peak serum chlorobutanol concentration was 83 µg/mL, a concentration similar to that in the previous case report¹⁹; however, the coadministration of morphine precludes the effects being attributed to chlorobutanol alone.

Ketamine is neurotoxic when administered intrathecally to animals.^106,107 The potential neurotoxic effects of chlorobutanol as a preservative in ketamine compared with preservative-free ketamine was studied in rabbits.¹⁰⁷ Forty rabbits were given 0.3 mL intrathecally of either 1% preservative-free ketamine, 1% ketamine, 0.05% chlorobutanol, or 1% lidocaine as control. The rabbits were observed and hemodynamically monitored for 8 days and then euthanized. Histologic evaluation of the spinal cord as well as for blood brain barrier (BBB) lesions was performed. Seven of the 10 rabbits given intrathecal chlorobutanol showed both white and grey matter histologic changes as well as diffuse BBB injury. No histologic changes were seen in either ketamine groups or the lidocaine group, and only one rabbit in each ketamine group had BBB injury. These results suggest chlorobutanol should not be administered intrathecally.¹⁰⁷

A case series of five patients were given intraarterial papaverine preserved with 0.5% chlorobutanol,¹⁴⁶ which is used to prevent cerebral vasospasm in patients with subarachnoid hemorrhage. Immediately after administration of papaverine in either the left, right, or bilateral anterior cerebral arteries, patients had an acute deterioration in neurologic status. Subsequent brain magnetic resonance imaging identified selective grey matter toxicity in the territories treated with papaverine. Postmortem brain histology analysis in one patient also identified grey matter changes. The authors state the absence of white matter changes is not consistent with ischemic infarction but suggest direct toxic effect of either the papaverine or chlorobutanol. The manufacturer of the papaverine stated that no other reports had been made and the papaverine used came from two different lots; therefore, it is unclear if an unidentified independent variable caused these effects, but the authors caution using intraarterial papaverine in patients with subarachnoid hemorrhage.¹⁴⁶

Ophthalmic Toxicity

Chlorobutanol is a commonly used preservative in ophthalmic preparations and is less toxic to the eye than benzalkonium chloride.¹²¹ Chlorobutanol increases the permeability of cells by impairing cell membrane structure.¹⁵⁸ An in vitro experiment using corneal epithelial cells harvested from human cadavers demonstrated arrested mitotic activity following chlorobutanol exposure.¹⁵⁸ At the commonly formulated concentration of 0.5%, chlorobutanol may cause eye irritation, most likely due to cellular contraction of epithelial microfilaments, cessation of normal cytokinesis, cell movement, and mitotic activity.⁴⁸ Degeneration of human corneal epithelial cells specifically manifested as membranous blebs, cytoplasmic swelling, and occasional breaks in the external cell membrane has also occurred at this concentration.⁴⁸

In general, there are three types of commercial intravenous lipid drug-delivery systems available: lipid emulsion, liposomal, and lipid complex (Table 55–5). Lipid emulsions are immiscible lipid droplets dispersed in an aqueous phase stabilized by an emulsifier (eg, egg, soy lecithin). Liposomes differ from emulsion lipid droplets in that they are vesicles comprised of one or more concentric phospholipid bilayers surrounding an aqueous core. Lipophilic drugs can be formulated for intravenous administration by partitioning them into the lipid phase of either an emulsion or liposome. Liposomes are capable of encapsulating hydrophilic xenobiotics within their aqueous core to exploit lipid pharmacokinetic properties.¹⁵³ Attaching a therapeutic drug to a lipid to form a lipid complex is another way to take advantage of lipid pharmacokinetics.

Lipid carriers are biocompatible because of their similarity to endogenous cell membranes. They can be created with stable lipid membranes resistant to hydrolysis or oxidation, to decrease toxicity, and to enhance therapeutic efficacy by altering drug pharmacokinetic and pharmacodynamic parameters. The biodistribution, and the rate of release and metabolism of a drug incorporated in a lipid formulation can be regulated by the type and concentration of oil and emulsifier used, pH, drug concentration dispersed in the medium, the size of the lipid particle, and the manufacturing process.^123,153 Intravenous formulations are usually isotonic and have a pH of 7 to 8.¹⁵³

The rate of clearance of a lipid carrier from the blood depends on its physicochemical properties and the molecular weight of the emulsifier. Electrically charged lipid carriers are removed more rapidly than neutral particles.^24,123 Smaller lipid particle size and high-molecular-weight emulsifiers decrease clearance. Stealth liposome formulations incorporate a polyethylene glycol coating that prevents rapid detection and clearance of liposomes by the reticuloendothelial system prolonging circulation time.¹²³ Active drug targeting can be achieved by conjugating antibodies or vectors to side chains on the emulsifier.^24,123 For a therapeutic drug available in more than one lipid-carrier formulation (eg, amphotericin B), it is important to note that any change in the lipid formulation can alter the drug’s pharmacokinetic, pharmacodynamic, and safety parameters; consequently, they are not equivalent dosage formulations (Chap. 57).

The physicochemical properties of lipid emulsions not only affect the therapeutic drugs carried by them, but the lipids themselves may also have direct pharmacologic effects on the central nervous¹⁷⁰ and immune ­systems.⁹³ Lipid fatty acid mediators can affect the membrane receptor channels of N-methyl-d-aspartate (NMDA) receptors, potentiating ­synaptic transmission.^{110,111,126,156} Dogs given a medium-chain triglyceride emulsion intravenous infusion developed dose-related central nervous system metabolic and neurologic effects, accompanied by electroencephalographic changes consistent with encephalopathy observed when serum octanoate concentration reached 0.5 to 0.9 mM.¹¹⁰ In an in vitro model, three of nine lipid emulsions tested (Abbolipid, 20% soya and safflower oil; Intralipid, 20% soya oil; and Structolipid, 20% structured triglycerides) demonstrated a dose-related activation of cortical neuronal NMDA receptor channels.¹⁷⁰ The lipid source for all but one (Omegaven, 10% fish oil) of the emulsions tested was made up solely or partially by soya oil. The authors could not explain why the other six lipid emulsions did not induce membrane currents. Adequate control for the nonlipid constituent contribution of these emulsions is lacking. In another in vitro study, the same authors found that NMDA-induced neuronal currents are reduced by an unknown factor in the aqueous portion of Abbolipid.¹⁷¹ This suggests that lipid emulsions may pharmacologically enhance the anesthetic effect of hypnotics such as propofol. The clinical relevance of these studies remains to be assessed.

Triglycerides in parenteral nutrition emulsions are implicated in altering the immune system, leading to an increased susceptibility to infection,^56,168 and altering lung function and hemodynamics in patients with acute respiratory distress syndrome.⁹³ Phospholipid activation of phospholipase A₂ may be an initiating cause.^56,93,168 However, it is not clear if these immunologic effects are a consequence of factors other than the lipid in the emulsion.

More recently, the sequestering properties of fat emulsions have been employed in the treatment of poisonings in both animal models and human case reports (Antidotes in Depth: A20).^11,125,145

The parabens, or parahydroxybenzoic acids, are a group of compounds widely employed as preservatives in cosmetics, food, and pharmaceuticals because of their bacteriostatic, fungistatic, and antioxidant properties (Table 55–6).¹⁴⁰ A survey conducted by the FDA identified the parabens as the second most common ingredients in cosmetic formulations, with water being the most common.⁹⁸ Parabens are often used in combination, because the presence of two or more parabens are synergistic.⁹⁸ Methylparabens and propylparabens are most commonly used.¹⁴⁰ Pharmaceutical paraben concentrations usually range from 0.1% to 0.3%.¹³⁴

Widespread usage of parabens since the 1920s has shown that they have a relatively low order of toxicity.⁹⁸ However, because of their allergenic potential they are currently considered less suitable for injectable and ophthalmic preparations.¹³⁴ Based on long-term animal studies, the WHO has set the total acceptable daily intake of ethylparabens, methylparabens, and propylparabens to be 10 mg/kg body weight.¹³⁴ In addition to allergic reactions, parabens have the potential to cause other adverse effects. Bilirubin displacement from albumin binding sites occurred with administration of methyl- and propylparabens preserved gentamicin when serum parabens concentrations were 3 to 15 µg/mL.⁴¹ Gentamicin alone has no effect on bilirubin displacement.⁹² Spermicidal activity was demonstrated in an in vitro study of human semen specimens exposed to local paraben concentrations of 1 to 8 mg/mL.¹⁵⁰ Possible interference with conception and potential adverse effects on fertility were not investigated.

More recently, concern has arisen regarding the potential estrogenic and antiandrogenic effects of the parabens and their common metabolite, p-hydroxybenzoic acid. Xenobiotics with these effects are commonly referred to as endocrine disrupting substances. It has been suggested that methylparaben is less toxic than butyl and benzyl-parabens with regard to oxidative stress and resultant cytotoxicity.^42,143 However, the clinical significance of these effects is not elucidated.^{32,43,131,132,164}

Phenol (carbolic acid, hydroxybenzene, phenylic acid, phenylic alcohol) is a commonly used preservative in injectable medications (Table 55–7). Phenol is a colorless to light pink, caustic liquid with a characteristic odor. When exposed to air and light, phenol turns a red or brown color.³⁸ Phenol exerts antimicrobial activity against a wide variety of microorganisms, such as Gram-negative and Gram-positive bacteria, mycobacteria, and some fungi and viruses.³⁸ Phenol is well absorbed from the gastrointestinal tract, skin, and mucous membranes, and is excreted in the urine as phenyl glucuronide and phenyl sulfate metabolites.³⁸ Although there are numerous reports of phenol toxicity following intentional ingestions or unintentional dermal exposures (Chap. 106), adverse reactions to its use as a pharmaceutical excipient are uncommon, most likely because of the small quantities used.³⁸

Cutaneous Absorption

Systemic toxicity from cutaneous absorption of phenol is reported. Ventricular tachycardia was observed in an 11 year-old boy following application of a chemical peel solution containing 88% phenol in water and liquid soap. The solution was applied to 15% of his body surface area for the treatment of xeroderma pigmentosum. Immediately following the onset of the ventricular tachycardia, the phenol-treated areas were irrigated, an infusion of 0.9% sodium chloride solution was begun, and two intravenous lidocaine boluses were given followed by a lidocaine infusion. The dysrhythmia persisted for 3 hours. The urinary phenol concentration the following day was 58.9 mg/dL.¹⁶² In a similar case, multifocal premature ventricular contractions were observed in a 10 year-old boy after application of a chemical peeling solution of 40% phenol, 0.8% croton oil in hexachlorophene soap, and water for the treatment of a giant hairy nevus.¹⁶⁹ The premature ventricular contractions were refractory to intravenous lidocaine but resolved with intravenous bretylium. No phenol concentrations were obtained to confirm systemic absorption. In a case series of 181 patients undergoing chemical face peeling with phenol-based solutions, 12 demonstrated cardiac dysrhythmias. This occurred more commonly in patients with comorbid diabetes mellitus, hypertension or treatment with antidepressants. These authors recommend prophylactic administration of proprandol prior to phenol application to mitigate these dysrhythmias citing a reduction in dysrhythmia incidence in their patients.⁹¹ Despite the risk of toxicity, phenol chemical peels are still used in some cases because phenol penetrates deep into tissues providing both long-lasting and good cosmetic results. Most commonly phenol chemical peels are used for deep acne scars and other severe skin disorders.

Drowsiness, respiratory depression, and blue-colored urine were noted in a 6 month-old infant 12 hours after topical application of magenta paint over most of the body for seborrheic eczema.¹³⁶ Magenta paint (also known as Castellani paint) was widely used for seborrheic eczema and contained 4% phenol, magenta, boric acid, resorcinol, acetone, and methylated spirit. Further investigation found that phenol was detected in urine samples of four of 16 other infants with seborrheic eczema who had approximately 11% to 15% of their body surface area painted with magenta paint for 2 days.

Polyethylene glycols (PEGs; Carbowax, Macrogol) include several compounds with varying molecular weights (200–40,000 Da).¹³⁰ They are typically available as mixtures designated by a number denoting their average molecular weight. PEGs are stable, hydrophilic substances, making them useful excipients for cosmetics, and pharmaceuticals of all routes of administration (Table 55–8). Pegylation, a process that modifies the pharmacokinetics of therapeutic liposomes and proteins (eg, peginterferon-α), is the most recent application of PEG. At room temperature, PEGs with molecular weights less than 600 are clear, viscous liquids with a slight characteristic odor and bitter taste. PEGs with molecular weights heavier than 1000 are soluble solids and range in consistency from pastes and waxy flakes to powders.¹³⁰ Commercially available products used for bowel cleansing preparations and whole bowel irrigation are solutions of PEG 3350 sometimes combined with electrolytes and known as PEG electrolyte lavage solution (PEG-ELS; Antidotes in Depth: A2).

The solid, high-molecular-weight PEGs are essentially nontoxic. Conversely, low-molecular-weight PEG exposures have caused adverse effects similar to the chemically related toxic alcohols ethylene and diethylene ­glycol²⁸ (Special Considerations: SC7).

Pharmacokinetics

High-molecular-weight PEGs (> 1000) are not significantly absorbed from the gastrointestinal tract, but low-molecular-weight PEGs may be absorbed when taken orally.^47,147,148 Topical absorption can occur when PEGs are applied to damaged skin.^22,154 Once in the systemic circulation, PEGs are mainly excreted unchanged in the urine⁴⁷; however, low-molecular-weight PEGs (eg, PEG 300, PEG 400) are partially metabolized by alcohol dehydrogenase to hydroxyacid and diacid metabolites. The pharmacokinetics of intravenously administered PEG 3350 has not been studied; however, it did not appear to have any systemic effects when unintentionally given by this route.¹³⁵

Nephrotoxicity

In rats fed various PEGs (200, 300, and 400) in their drinking water for 90 days, a solution of 8% PEG 200 produced renal tubular necrosis in all of the animals, followed by death within 15 days; however, a 4% PEG 200 solution resulted in only two of nine rats dying within 80 days. A 16% PEG 400 solution killed all animals within 13 days; however, both 8% and 4% PEG 400 solutions had no observable effect except for a decrease in kidney weight when compared to control animals.¹⁴⁹ A more recent study administering daily high dose PEG 400 intravenously, up to 8.45 g/kg/day, in a canine model failed to show serious renal toxicity. However, edema of kidney cells and increased glomerular volume occurred at these dosages but were reversible.⁹⁵ Acute tubular necrosis has been reported with oliguria, azotemia, and an anion gap metabolic acidosis following oral and topical exposures to low-molecular-weight PEGs (200 and 300). Acute kidney failure occurred in a 65 year-old man with a history of alcohol abuse and seizure disorder after ingestion of the contents of a lava lamp containing 13% PEG 200.⁴⁹ About 48 hours after admission (approximately 50–72 hours postingestion), the patient became oliguric with an anion gap metabolic acidosis and acute kidney failure. Blood sample analysis confirmed traces of the lava lamp fluid; no traces were detected in the urine. After clinical complications from ethanol withdrawal and aspiration pneumonitis, the patient was discharged 3 months later with residual kidney dysfunction attributed to the PEG component of the lamp contents. Acute tubular necrosis was noted on autopsy of six burn patients treated with a topical antibiotic cream in a PEG 300 base.^22,154 Mass spectrometry detected hydroxyacid and diacid metabolites in serum and urine samples. Oxalate crystals were seen in two cases. These effects were reproduced with the topical application of PEG for 7 days to rabbits with full-thickness skin defects.¹⁵⁴

Neurotoxicity

There are reports of neurologic complications, such as paraplegia and transient bladder paralysis, following intrathecal corticosteroid injections containing 3% PEG as a vehicle.^14,18 In an in vitro experiment, rabbit vagus nerves were exposed to concentrations of PEG 3350 ranging from 3% to 40% for one hour.¹⁴ A total of 3% and 10% PEG had no effect on nerve action potential amplitude or conduction velocity. A dose of 20% and 30% PEG significantly slowed nerve conduction and had varying effects on the amplitudes of action potentials. Forty percent PEG completely abolished action potentials. These changes were reversible and thought to be related to PEG-induced osmotic effects. More recently, the administration of PEG 1800 is being studied as a potential therapy for spinal cord injury by repairing damaged axons through cellular fusion of damaged cells following the short-term (2 minutes) application, in a guinea pig model. This increases compound action potential conduction.¹⁴⁴ Interestingly, administering a similar dose of PEG continuously for 25 minutes decreased compound action potentials approximately 64% in both damaged and non-damaged isolated mammalian spinal cords suggesting dose-response toxicity.³⁶

Fluid, Electrolyte, and Acid–Base Disturbances

Hyperosmolality was reported in three patients with burn surface areas ranging from 20% to 56% following repeated applications of Furacin, a topical antibiotic dressing containing 63% PEG 300, 32% PEG 4000, and 5% PEG 1000.²² PEG produces an osmotic effect that is greater than expected for its molecular weight.¹⁴¹ It is theorized that PEG increases osmolality by sequestering water through hydrogen binding, which reduces the availability of water to interact with solutes, thus increasing the chemical and osmotic activity of the solute. Hyperosmolality following the administration of a PEG-containing substance may suggest systemic PEG absorption.

Two cases of metabolic acidosis were reported following administration of therapeutic dosages of an intravenous nitrofurantoin solution containing PEG 300.¹⁵⁵ Similarly, an otherwise unexplained increased anion gap was reported in three patients being treated with a topical PEG-based burn cream.²³ Metabolism of the lower-molecular-weight PEGs by alcohol dehydrogenase to hydroxyacid and diacid metabolites can explain the metabolic acidosis.⁷⁴

Propylene glycol (PG), or 1,2-propanediol, is a clear, colorless, odorless, sweet, viscous liquid employed in numerous pharmaceuticals (Table 55–9), foods, and cosmetics. Propylene glycol is used as a solvent and preservative with antiseptic properties similar to ethanol. The WHO has set the daily allowable intake of PG at a maximum of 25 mg/kg,¹⁷² or 1.75 g/d for a 70-kg person.

Pharmacokinetics

Propylene glycol is rapidly absorbed from the gastrointestinal tract following oral administration and has a volume of distribution of approximately 0.6 L/kg.^108,151 When applied to intact epidermis, the absorption of PG is minimal. Percutaneous absorption may occur following application to damaged skin (eg, extensive burn surface areas). Approximately 12% to 45% of PG is excreted unchanged in the urine,⁴⁶ the remainder is hepatically metabolized sequentially by alcohol dehydrogenase to lactaldehyde, which is metabolized further by aldehyde dehydrogenase to lactic acid. Lactic acid is also formed by another metabolite, methylglyoxal.¹²⁰ Lactic acid may be oxidized to pyruvic acid and then to carbon dioxide and water.¹²⁰ The terminal half-life of propylene glycol is reported to be between 1.4 and 5.6 hours in adults and as long as 16.9 hours in neonates.^46,153

Cardiovascular Toxicity

Intravenous preparations of phenytoin contain 40% PG to facilitate the dissolution of phenytoin. Nine years after intravenous phenytoin became available, several deaths were attributed to the rapid administration of phenytoin used for the treatment of cardiac dysrhythmias.^63,160,182

Cardiovascular effects reported in these cases included hypotension, bradycardia, widening of the QRS interval, increased amplitude of T waves with occasional inversions, and transient ST elevations. Studies in cats¹⁰⁰ and calves⁶⁷ confirmed PG as the cardiotoxin. Bradycardia and depression of atrial conduction were not observed in cats pretreated with atropine, or in those with vagotomy following rapid intravenous infusion of PG, suggesting that these effects are vagally mediated.¹⁰⁰ Amplification of the QRS complex was noted in these same pretreated cats, also suggesting a direct cardiotoxic effect of PG. Similar results were reported in calves pretreated with atropine that received oxytetracycline in a PG vehicle.⁶⁷

Neurotoxicity

Smaller infants appear to have a decreased ability to clear PG when compared with older children and adults.¹⁰¹ An increased frequency of seizures was reported in low-birth-weight infants who received PG 3 g daily in a parenteral multivitamin preparation.¹⁰¹ Seizures developed in an 11 year-old boy receiving long-term oral therapy with vitamin D dissolved in PG.⁷ Serum calcium, magnesium, electrolytes, and blood glucose were normal. Seizures abated after the product was discontinued. Propylene glycol possesses inebriating properties similar to ethanol. Central nervous system depression was reported following an intentional oral ingestion of a PG-containing product.¹⁰⁸

A black-box warning was added to the product information for amprenavir (Agenerase), an oral protease inhibitor solution, because of concerns over its high PG (550 mg/mL) vehicle content.¹³⁸ The recommended daily dosage of amprenavir supplies 1650 mg/kg/day of PG. A 61 year-old man experienced visual hallucinations, disorientation, tinnitus, and vertigo after receiving a 750-mg dose (474 mg/kg PG) of amprenavir solution.⁸⁵

Ototoxicity

Otic preparations can contain up to 94% PG in solutions and 10% in suspensions as part of their vehicles.⁵² In animal studies, application of high concentrations of PG (> 10%) to the middle ear can produce hearing impairment^113,114,166 and morphologic changes, including tympanic membrane perforation, middle ear adhesions, and cholesteatoma.^113,154,177 Although the effects of PG in the human middle ear have not been studied, all medications applied to the external ear canal are contraindicated in patients with perforated tympanic membranes.

Fluid, Electrolyte, and Acid–Base Disturbances

Patients receiving continuous or large intermittent quantities of medications containing PG can develop high PG concentrations, particularly those with renal or hepatic insufficiency.^27,46 Propylene glycol–induced electrolyte and metabolic disturbances are evidenced by hyperosmolarity, and an elevated osmolar gap attributed to the osmotically active properties of PG. In most cases, an elevated anion gap, with an otherwise unexplained elevated lactate concentration, is also present. Metabolic acidosis and hyperlactatemia result from PG metabolism.²⁶ These adverse effects are typically reported with intravenous preparations such as lorazepam,^5,80,179 diazepam,¹⁷³ etomidate,¹⁶³ nitroglycerin,⁴⁶ pediatric multivitamins,⁶⁵ and topical silver sulfadiazine.^12,53,89

Systemic absorption of PG from topical application of silver sulfadiazine cream⁵³ resulted in hyperosmolality in patients with burn surface areas greater than 35% of their body.^12,53,89 In one study, nine of 15 burn patients had osmolar gaps (> 12) after application of the cream.⁸⁹

Hyperosmolarity occurred in five infants receiving a parenteral multivitamin that provided a daily PG dose of 3 g.⁶⁵ After 12 days, one premature infant had a PG concentration of 930 mg/dL and an osmolar gap of 136. Anion gap and lactic acid concentrations were normal. In a study, 11 intubated children aged 1 to 15 months who were receiving continuous lorazepam infusions over 3 to 14 days, accumulated serum PG concentrations of 17 to 226 mg/dL did not result in significant increases in osmolar gap or serum lactate concentrations from baseline.³³ This was attributed to normal renal function and the low cumulative PG doses received (mean, 60 g).

Several small studies have found a strong correlation between elevated PG concentrations and increased osmolar gap measurements in critically ill patients receiving intravenous lorazepam and/or diazepam.^{6,174,178,179} An osmolar gap greater than 10 has been suggested as a marker for potential PG toxicity and also indicates when to consider obtaining a serum PG concentration.¹⁷⁸ An osmolar gap of 20 corresponds to a serum PG concentration of approximately 48 mg/dL.⁶ This equation should be used cautiously, as larger, more comprehensive studies are needed to validate it. There are rare cases where PG accumulation did not result in an osmolar gap.^66,179 In addition, elevated anion gap measurements and lactate concentrations occur. As PG toxicity can mimic sepsis in these critically ill patients, sepsis should always be considered as the potential etiology of increased lactate, hypotension, and worsening renal function when considering PG toxicity. Both hemodialysis and fomepizole have been used to treat PG toxicity.^124,181

Nephrotoxicity

Human proximal tubular cells exposed in vitro to PG concentrations of 500 to 2000 mg/dL exhibited significant cellular injury and membrane damage within 15 minutes of exposure.¹¹⁶ Repeated exposure for up to 6 days produced dose-dependent toxic effects at lower concentrations (76, 190, and 380 mg/dL).¹¹⁵

The chronic administration of PG may contribute to proximal tubular cell damage and subsequent decreased kidney function. In a retrospective study of eight patients who developed elevations in serum creatinine concentration while receiving continuous lorazepam infusions, serum creatinine rose within 3 to 60 days (median, 9 days).¹⁷⁹ The magnitude of serum creatinine rise was found to correlate with the serum PG concentration and duration of infusion. Serum creatinine decreased within 3 days of discontinuing the infusion. Patients with chronic kidney disease are at greater risk for accumulating PG because 45% of PG is eliminated unchanged by the kidneys⁴⁶; the remainder is metabolized by the liver. Caution should be used when prolonged administration of a PG-containing medication is necessary in the presence of renal or hepatic dysfunction.¹¹⁶

Propylene glycol induced renal tubular necrosis has been reported in several cases. Daily PG vehicle dosages of 11 to 90 g/day over 14 days was associated with rising serum creatinine concentrations (0.7–2.1 mg/dL), elevated serum lactate concentrations, osmolar and anion gaps, and a serum PG concentration of 21 mg/dL.¹⁸⁰ Urine sediment analysis revealed numerous granular, muddy-brown-colored casts and no eosinophils, suggesting an acute renal tubular necrosis. Kidney biopsy and electron microscopy showed extensive dilation of the proximal renal tubules, with swollen epithelial cells and mitochondria. Numerous vacuoles containing debris were also noted. A kidney biopsy of another case with a serum PG concentration of 30 mg/dL showed disrupted brush borders of the proximal renal tubules after a sudden rise in serum creatinine concentration (3.1 mg/dL), nonoliguric kidney failure, and metabolic acidosis. This was attributed to an average daily PG dose of 70 g for 17 days.⁷²

Sorbitol (d-glucitol) is widely used in the pharmaceutical industry as a sweetener, moistener agent, and as a diluent (Table 55–10). Sorbitol occurs naturally in the ripe berries of many fruits, trees, and plants, and was first isolated in 1872 from the berries of the European mountain ash (Sorbus aucuparia).¹¹⁸ It is particularly useful in chewable tablets because of its pleasant taste. In addition, it is widely used by the food industry in chewing gums, dietetic candies, foods, and enteral nutrition formulations. Sorbitol is approximately 50% to 60% as sweet as sucrose.¹¹⁸

Pharmacokinetics

Unlike sucrose, sorbitol is not readily fermented by oral microorganisms and is poorly absorbed from the gastrointestinal tract. Any absorbed sorbitol is metabolized in the liver to fructose and glucose.¹¹⁸ Sorbitol has a caloric value of 4 kcal/g and is better tolerated by diabetics than sucrose; however, because some of it is metabolized to glucose, it is not unconditionally safe for people with diabetes and is obviously not “dietetic”.¹¹⁸

There is a concern of potentially fatal toxicity for individuals with hereditary fructose intolerance (HFI) receiving sorbitol-containing xenobiotics.⁵⁴ HFI is an autosomal recessive disorder caused by a deficiency of fructose-1,6-bisphosphonate aldolase in the liver, kidney, cortex, and small intestine.⁸⁶ This results in the accumulation of fructose-1-phosphate, which prevents glycogen breakdown and glucose synthesis causing hypoglycemia. The prevalence of HFI is most commonly reported to be one in 20,000 persons, but can range between one in 11,000 and one in 100,000.^2,84,86

In individuals with HFI, the prolonged administration of sorbitol, fructose, or sucrose can result in death from liver or kidney failure.^37,142 Dietary exclusion of fructose, sucrose, and sorbitol prevents the adverse effects. This condition should not be confused with the more common disorder of dietary fructose intolerance, which is caused by a defect in the glucose-transport protein 5 system. This leads to the breakdown of fructose to carbon dioxide, hydrogen, and short-chain fatty acids by colonic bacteria, resulting in abdominal pain and bloating.⁹² Dietary fructose intolerance symptoms are minimized by limiting sorbitol, fructose, and sucrose in the diet.

Gastrointestinal Toxicity

In large dosages, sorbitol can cause abdominal cramping, bloating, flatulence, vomiting, and diarrhea. Sorbitol exerts its cathartic effects by its osmotic properties, resulting in fluid shifts within the gastrointestinal tract. Iatrogenic osmotic diarrhea is reported following administration of many different liquid medication formulations containing sorbitol.^76,102 In a human volunteer study, 42 healthy adults ingested 10 g of a sorbitol solution. Sorbitol intolerance was detected in up to 55% of participants.⁸³ One theoretical explanation for why all participants did not experience the gastrointestinal adverse effects is unrecognized dietary fructose intolerance. Diarrhea resulting from sorbitol-containing medications is common and often overlooked as a possible etiology.^31,73 Ingestion of large quantities of sorbitol (> 20 g/day in adults) is not recommended (Antidotes in Depth: A2).¹¹⁸

Thimerosal (Merthiolate, Mercurothiolate), or sodium ethylmercurithiosalicylate, is an organic mercury compound that is approximately 49% ­elemental mercury (Hg^o) by weight.^137,167 It is metabolized to ethylmercury and thiosalicylate. Thimerosal has a wide spectrum of antibacterial activity at concentrations ranging from 0.01 to 0.1%; however, higher concentrations are sometimes also used.^88,112 Thimerosal has been widely used as a preservative since the 1930s in contact lens solutions, biologics, and vaccines, particularly those in multidose containers (Table 55–11). The use of thimerosal, which is necessary for the production process of some vaccines (eg, pertussis, influenza), may leave trace amounts in the final product.¹⁰ High-dose thimerosal exposure has resulted in neurotoxicity and nephrotoxicity. Although concerns exist regarding infant exposure to low-dose thimerosal through vaccinations and its effects on neurodevelopment, including possible links to causes of autism,¹⁷ these concerns are unfounded (Chap. 98).⁴⁴

Because specific guidelines for ethylmercury exposure have not been developed, regulatory guidelines for dietary methylmercury exposure were applied to monitor ethylmercury exposure from injected thimerosal-containing vaccines. Methylmercury is a similar, but more toxic, organic mercury compound (Chap. 98). Maximum daily recommended methylmercury exposures range from 0.1 µg Hg/kg (US Environmental Protection Agency {EPA}) to 0.47 µg Hg/kg (WHO).^3,30,35

An FDA review of thimerosal-containing vaccines revealed that some infants, depending on the immunization schedule, vaccine formulations, and infant’s weight, might be exceeding the EPA exposure limit of 0.1 µg Hg/kg/day for methylmercury. Over the first 6 months of life, a total cumulative dose of up to 187.5 µg Hg total from thimerosal-containing vaccines was possible. The US Public Health Service and the American Academy of Pediatrics jointly responded by recommending the preemptive reduction or removal of thimerosal from vaccines wherever possible.^3,29 The WHO and European regulatory bodies have made similar recommendations.⁵⁵ To date, thimerosal has been removed from most US-licensed immunoglobulin products. All vaccines routinely recommended for children younger than 7 years of age are either thimerosal-free or contain only trace amounts (< 0.5 µg Hg/dose), with the exception of some inactivated influenza vaccines. Multidose vials requiring thimerosal preservative remain important for immunization programs in developing countries due to lack of consistent ability to refrigerate vaccines. Although efforts continue to eliminate all sources of mercury exposure, complete elimination of thimerosal from all vaccines is unlikely in the near future.¹⁰ When a thimerosal-containing ­vaccine is the only alternative, the benefits of vaccination far exceed any theoretical risk of mercury toxicity.¹¹⁹

Prior to thimerosal use in pharmaceuticals, evidence for its safety and effectiveness was provided in several animal species and in 22 humans.¹²⁹ Only limited data exist on infant mercury exposure from thimerosal-containing vaccines. Clinical studies that assess the effects of thimerosal exposure on neurodevelopment and renal and immunologic function are lacking. Based on a comprehensive review of epidemiologic data from the United States,^{34,58,61,157,167} Denmark,^104,105 Sweden,¹⁵² and the United Kingdom,^5,75 the Institute of Medicine’s Immunization Safety Review Committee,¹¹⁹ the Global Advisory Committee on Vaccine Safety,¹⁷⁶ and the European Agency for the Evaluation of Medicinal Products⁵⁰ have all concluded that no causal relationship exists between thimerosal-containing vaccines and autism. Continued surveillance of autistic spectrum disorders as thimerosal use declines will be conducted to evaluate any associated trends.

Pharmacokinetics

Limited pharmacokinetic data exist for thimerosal and ethylmercury. Once absorbed, thimerosal breaks down to form ethylmercury and thiosalicylate. Some ethylmercury further decomposes into inorganic mercury in the blood, and the remainder distributes into kidney and, to a lesser extent, brain tissue.^104,105 Because of its longer organic chain, ethylmercury is less stable and decomposes more rapidly than methylmercury, leaving less ethylmercury available to enter kidney and brain tissue.¹⁰⁴ Ethylmercury crosses the blood–brain barrier by passive diffusion.¹⁰⁵ Intracellular ethylmercury decomposes to inorganic mercury, which accumulates in kidney and brain tissues.¹⁰⁵ The half-life of thimerosal is estimated to be about 18 days.¹⁰⁶ Thimerosal is eliminated in the feces as inorganic mercury (Chap. 98).¹²⁸

Mercury or Thimerosal Toxicity

Oral Administration.

A case report described a 44 year-old man who ingested 5 g (83 mg/kg) of thimerosal in a suicide attempt; within 15 minutes he began vomiting spontaneously. Gastric lavage was performed and chelation therapy begun with dimercaptopropane sulfonate. Gastroscopy revealed a hemorrhagic gastritis. Polyuric acute kidney injury was noted on the day of admission and persisted for 40 days. Four days after admission, the patient developed fever and a maculopapular exanthem attributed to thimerosal. The patient also developed an autonomic and ascending peripheral polyneuropathy that persisted for 13 days. Chelation therapy was continued for a total of 50 days with dimercaptopropane sulfonate followed by succimer. Elevated blood and urine mercury concentration persisted for more than 140 days. The patient was discharged 148 days following the ingestion with only sensory defects in his toes. No other neurologic sequelae were noted.¹²⁷

Oral absorption of thimerosal resulted in the fatal poisoning of an 18 month-old girl from the intraotic instillation of a solution containing 0.1% thimerosal and 0.14% sodium borate. Tympanostomy tubes placed one year earlier allowed the irrigation solution to flow through the auditory tube into the nasopharynx, and subsequently to be swallowed and absorbed through the oral mucosa and gastrointestinal tract. A total of 1.2 L of solution (500 mg Hg) was instilled over a 4 week period, resulting in severe mercury poisoning. Four days after admission, the serum mercury concentration was 163 µg/dL. The patient also received 1.7 g of boric acid. It is unclear what contribution, if any, the boric acid made to the serum mercury concentration. Chelation therapy with N-acetyl-d-penicillamine was initiated on day 51. Despite increased urinary mercury concentrations following administration of the N-acetyl-d-penicillamine, her neurologic function and blood mercury concentrations remained unchanged. The child died 3 months after admission. An autopsy was not performed.¹³⁷

Intramuscular Administration.

Urine mercury concentrations of 26 patients with hypogammaglobulinemia, who received weekly intramuscular immunoglobulin G (IgG) replacement therapy preserved with 0.01% thimerosal were studied. The dosages of IgG ranged from 25 to 50 mg/kg, containing 0.6 to 1.2 mg of mercury per dose.⁶⁸ The total estimated dose of mercury administered ranged from 4 to 734 mg over a period of 6 months to 17 years. Urine mercury concentrations were elevated in 19 patients, ranging from 31 to 75 µg/L; however, no patients had clinical evidence of chronic mercury toxicity.⁶⁸

Six cases of severe mercury poisoning resulting in four deaths were reported following the intramuscular administration of chloramphenicol preserved with thimerosal. A manufacturing error produced vials containing 510 mg of thimerosal (250 mg Hg) instead of 0.51 mg per vial. Two adults received 4 g and 5.5 g of mercury each and four children received 0.2 to 1.8 g each. All six patients had extensive tissue necrosis at the site of injection. Fever, altered mental status, slurred speech, and ataxia were noted. Autopsy identified widespread degeneration and necrosis of the renal tubules; however, creatine kinase concentrations were not reported, so pigment-induced nephrotoxicity cannot be excluded. Elevated mercury concentrations were found in the injection site tissues, and in the kidneys, livers, and brains.⁸

Topical Administration.

Thirteen infants were exposed to nine to 48 topical applications of a 0.1% thimerosal tincture for the treatment of exomphalos. Analysis for elevated mercury concentrations was performed in 10 of 13 infants who unexpectedly died. Mercury concentrations were determined in various tissues from six of the infants. Mean tissue concentrations in fresh samples of liver, kidney, spleen, and heart ranged from 5152 to 11,330 ppb, suggesting percutaneous absorption from these repeated topical applications.⁵¹

Ophthalmic Administration.

Nine patients undergoing keratoplasty were exposed to a contact lens stored in a solution containing 0.002% thimerosal.¹⁷⁵ After 4 hours, the lens was removed and mercury concentrations of the aqueous humor and excised corneal tissues were determined. Mercury concentrations were elevated in both aqueous humor (range, 20–46 ng/mL higher) and corneal tissues (range, 0.6–14 ng/mL higher) as compared with eyes that had not been fitted with contact lenses. Only residual amounts of mercury remained on the contact lenses after 4 hours of wear. The authors noted that although the aqueous humor concentrations were in the same range as those measured in 10 patients with vision loss from systemic mercury poisoning (11–104 ng/mL), adverse effects did not occur.

A possible drug interaction between orally administered tetracyclines and thimerosal was reported to result in acute, varying degrees of eye irritation in contact lens wearers using thimerosal-containing contact lens solutions who started treatment with tetracycline.⁴⁰

• The benefits of pharmaceutical excipients include improved xenobiotic solubility, stability, and palatability, antimicrobial activity, the availability of various dosage forms, the provision of products with long-term storage, and the availability of multiple-dose packaging. While excipients are essential and effective, they are suggested to possess no pharmacologic or toxicologic properties but may actually be responsible for severe—and sometimes fatal—adverse effects.

• The toxicity of pharmaceutical excipients should be considered for patients requiring high doses or prolonged administration of any medication containing excipients, particularly those additives known to have toxicities.

• Under circumstances in which there is no option but to continue treating a patient with a particular xenobiotic, switching to a preservative-free product, or to another brand without the offending excipient, may obviate the need for discontinuation of an effective xenobiotic. In addition to inherent toxicities, many excipients may also be responsible for allergic reactions.

• In the majority of cases, pharmaceutical excipients are safe and effective, and their benefits far exceed their potential for adverse effects when properly administered.

References