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Elixir sulfanilamide

Elixir sulfanilamide was a liquid dosage form of the sulfonamide antibiotic sulfanilamide, manufactured and distributed by the S.E. Massengill Company in 1937 to provide an alternative for patients unable to swallow tablets.^[1] The formulation dissolved sulfanilamide in diethylene glycol—a sweet-tasting but highly nephrotoxic solvent—without prior toxicity testing in animals or humans, leading to rapid onset of symptoms including nausea, anuria, and death from acute renal failure in over 100 consumers, predominantly children.^[2]^[3] The incident unfolded after the company, responding to physician requests for a palatable liquid amid sulfanilamide's popularity against bacterial infections like streptococcal throat, produced approximately 1,100 gallons across 10 lots in Bristol, Tennessee, and shipped it nationwide without verifying the solvent's safety, despite prior knowledge of diethylene glycol's hazards from industrial uses.^[1] Under the 1906 Pure Food and Drug Act, which mandated only purity and accurate labeling rather than efficacy or safety demonstrations, the elixir evaded premarket scrutiny; the U.S. Food and Drug Administration (FDA) could only intervene post-distribution, ultimately recalling remaining stock but failing to prevent 105 confirmed fatalities.^[4]^[5] The tragedy exposed critical regulatory gaps, prompting congressional hearings that highlighted causal failures in pharmaceutical diligence and solvent selection, and directly catalyzed the Federal Food, Drug, and Cosmetic Act of 1938, which imposed mandatory safety proofs before interstate marketing.^[6] Massengill's president acknowledged oversight in assuming palatability equated safety, resulting in a misbranding fine but no criminal liability for deaths, underscoring the era's deference to industry self-regulation over empirical validation.^[7]^[3]

Background on Sulfanilamide

Discovery and Early Development

Sulfanilamide, chemically known as 4-aminobenzenesulfonamide, was first synthesized in 1908 by Austrian chemist Paul Gelmo as part of his doctoral dissertation at the Technische Hochschule in Vienna, though its potential therapeutic value remained unrecognized at the time.^[8] The compound's antibacterial properties emerged from research on azo dyes conducted in the early 1930s by Gerhard Domagk at IG Farbenindustrie's Bayer laboratories in Germany. In 1932, Domagk demonstrated that Prontosil—a sulfonamide-containing red dye—effectively protected mice against lethal streptococcal infections when administered parenterally, marking the first evidence of chemotherapeutic activity against bacterial pathogens in vivo.^[9]^[10] Prontosil's clinical potential was confirmed in 1935 when it successfully treated severe human infections, including erysipelas and puerperal sepsis, leading to its rapid commercialization in Europe.^[9] That same year, a team at the Pasteur Institute in Paris, including Jacques and Therese Tréfouël, Daniel Bovet, and Federico Nitti, identified sulfanilamide as the active metabolite responsible for Prontosil's efficacy; the dye moiety proved inert in vitro, but enzymatic cleavage in vivo released the simpler sulfanilamide molecule, which inhibited bacterial folate synthesis.^[11] This breakthrough, confirmed by further studies including Arthur Fuller's 1937 work demonstrating sulfanilamide's independent activity, shifted focus to direct synthesis and testing of the compound itself.^[11]^[8] Early development accelerated in 1936, with British researcher Leonard Colebrook initiating clinical trials of oral sulfanilamide for puerperal fever (childbed fever) at Queen Charlotte's Hospital in London, achieving dramatic reductions in mortality from over 20% to near zero in treated cases.^[12] By 1937, sulfanilamide was endorsed for streptococcal infections following animal and human safety assessments showing low toxicity at therapeutic doses, prompting widespread adoption in the United States and Europe for treating pneumonia, meningitis, and wound infections.^[4] This era saw sulfonamides hailed as "miracle drugs," contributing to a 28% drop in U.S. infectious disease mortality post-introduction, though initial enthusiasm overlooked emerging resistance and hypersensitivity risks.^[13]

Therapeutic Applications and Efficacy

Sulfanilamide served as a foundational sulfonamide antibiotic, primarily applied to treat bacterial infections susceptible to its bacteriostatic effects, including streptococcal conditions such as puerperal sepsis, septicemia, and childbed fever, as well as pneumococcal pneumonia, meningococcal meningitis, tonsillitis, bacillary dysentery, gonorrhea, and urinary tract infections.^[14]^[15] Its spectrum encompassed most gram-positive bacteria, such as Streptococcus pyogenes and Staphylococcus aureus, and select gram-negative organisms like Escherichia coli and Klebsiella species, though it showed limited activity against intrinsically resistant pathogens like Pseudomonas aeruginosa.^[15] The drug's efficacy derived from its structural similarity to para-aminobenzoic acid (PABA), enabling competitive inhibition of dihydropteroate synthase and disruption of bacterial folic acid biosynthesis, a pathway absent in humans who obtain folate exogenously.^[15] Early clinical observations in the 1930s, building on animal models where it prevented lethal streptococcal infections, confirmed its potency in humans; for instance, treatment reduced mortality in puerperal sepsis from 20-25% to 4-8%.^[14] By 1937, sulfanilamide in tablet and powder forms had demonstrated dramatic curative outcomes against streptococcal infections, establishing it as a revolutionary agent prior to the elixir formulation's introduction.^[14] While initial adoption yielded high success rates in severe infections, efficacy waned over time due to bacterial resistance mechanisms, such as plasmid-mediated folate bypass pathways, and was further constrained by the drug's inability to eradicate pathogens capable of exogenous folate uptake.^[15] Nonetheless, its historical validation through observational studies and wartime applications, including wound prophylaxis, underscored sulfonamides' role in markedly lowering infection-related mortality before penicillin's dominance.^[14]

Formulation and Production

Massengill Company's Approach

In June 1937, a salesman for the S.E. Massengill Company reported demand from physicians in southern U.S. states for a liquid form of sulfanilamide, as the existing powder and tablet versions were unsuitable for young children and others unable to swallow solids.^[16] The company's chief chemist, Harold Cole Watkins, was tasked with formulating an elixir, leading to the development of Elixir Sulfanilamide using diethylene glycol as the primary solvent at roughly 70% concentration to dissolve the poorly water-soluble sulfanilamide, with added raspberry flavoring for palatability.^[16] Diethylene glycol was chosen for its solvency, low cost, sweet taste, and availability as an industrial antifreeze, though its toxicity as a pharmaceutical vehicle had not been evaluated by Massengill; alternatives like propylene glycol were not pursued, reportedly due to higher expense and limited supply at the time.^[16]^[6] The manufacturing process involved dissolving sulfanilamide in diethylene glycol, incorporating flavorings, and filtering the mixture, followed by quality control checks limited to organoleptic properties—appearance, fragrance, and taste—in the company's laboratory; no pharmacological efficacy tests, stability assessments, or toxicity studies were conducted on the solvent, vehicle, or final product, reflecting the absence of premarket safety requirements under the Federal Food, Drug, and Cosmetic Act of 1906, which focused on labeling and adulteration rather than novel formulation safety.^[16]^[4] Production commenced in early September 1937, yielding 240 gallons distributed in 633 shipments nationwide to wholesalers, retailers, and physicians over the following weeks, with labeling as an "elixir" implying an alcohol base per pharmaceutical convention, though it contained none.^[16] Company president Samuel Evans Massengill later asserted that the firm had met a legitimate medical demand without foreseeably harmful results, stating, "My chemists and I deeply regret the fatal results, but there was no error in the manufacture of the product... not once could have foreseen the unlooked-for results. I do not feel that there was any responsibility on our part."^[16] Watkins, upon learning of the deaths, ingested the elixir himself and died by suicide on October 18, 1937.^[16] The approach prioritized rapid market response to competition—other firms like Sharp & Dohme and Merck offered liquid sulfanilamides using safer solvents like alcohol or glycerin—over independent verification of the solvent's safety, a decision enabled by regulatory gaps that permitted interstate shipment without federal oversight of therapeutic formulations.^[16]^[17]

Choice of Solvent and Manufacturing Process

The S.E. Massengill Company developed Elixir Sulfanilamide in response to physician requests for a liquid dosage form of the drug, particularly from southern states where tablets were deemed less suitable for certain patients, including children.^[16] Sulfanilamide's limited solubility in water (approximately 1:60 parts) and insufficient dissolution in ethanol alone necessitated a more effective solvent to achieve the desired concentration of about 3 grams per fluid ounce.^[1] ^[18] Chief chemist Harold Watkins experimented with potential solvents and selected diethylene glycol (DEG) for its strong solvency properties toward sulfanilamide, hygroscopic nature, low viscosity, sweet taste that aided palatability, and relative inexpensiveness compared to alternatives like propylene glycol.^[16] ^[19] DEG had prior non-pharmaceutical uses, such as in cosmetics and antifreeze, but its oral toxicity had not been rigorously evaluated for human consumption.^[1] The company did not conduct animal toxicity studies on the formulation, as premarket safety testing was not mandated by federal law in 1937, and internal checks focused solely on organoleptic qualities like flavor, appearance, and fragrance.^[16] ^[4] The manufacturing process was straightforward: sulfanilamide powder was dissolved in DEG to form the base vehicle, comprising approximately 72% DEG by volume, with additions of saccharin for sweetness and raspberry flavoring to improve taste without alcohol, despite the "elixir" label conventionally suggesting an ethanolic solution.^[18] ^[20] Each fluid ounce contained 40 grains (about 2.6 grams) of sulfanilamide in this solvent mixture, yielding a clear, raspberry-scented liquid.^[18] Batches were prepared in the company's Bristol, Tennessee, facility, with a total production of 240 gallons distributed via 633 shipments to physicians and pharmacies across 26 states, without sterility or stability testing beyond basic dissolution verification.^[16] ^[19] This expedited approach prioritized rapid market entry amid demand for the newly popular antibacterial agent over comprehensive safety validation.^[3]

The 1937 Crisis

Initial Distribution and Marketing

In June 1937, a salesman for the S.E. Massengill Company reported demand in southern U.S. states for a liquid form of sulfanilamide, as some patients, including children, struggled to swallow tablets or capsules.^[21] The company's chief chemist, Harold Watkins, formulated Elixir Sulfanilamide by dissolving sulfanilamide powder in diethylene glycol, a sweet-tasting solvent chosen for its ability to create a palatable, non-alcoholic liquid without further purification or toxicity testing.^[21] The product was produced in Bristol, Tennessee, yielding 240 gallons in total.^[21]^[2] Distribution commenced in early September 1937, with 633 shipments sent nationwide across at least 15 states, primarily through company sales representatives (detail men) who supplied it to physicians and, in some cases, drugstores.^[21]^[2] Initial emphasis was placed on southern markets where demand originated, facilitating rapid uptake by doctors prescribing it for streptococcal infections and other bacterial conditions.^[21] Marketing targeted physicians via direct sales efforts, positioning the elixir as a convenient, easy-to-administer alternative to solid dosage forms, leveraging the established efficacy of sulfanilamide while implying palatability through the traditional "elixir" nomenclature, which conventionally denoted alcohol-based solutions.^[21] No premarket safety evaluation of the vehicle was conducted or required under the 1906 Pure Food and Drugs Act, which focused solely on labeling and adulteration rather than pharmacological safety.^[2] The company's prior success with tablet and capsule sulfanilamide since 1935 supported confident promotion without formulation-specific trials.^[2]

Onset of Adverse Effects

The adverse effects of Elixir Sulfanilamide manifested within days of ingestion, primarily as acute kidney injury due to diethylene glycol toxicity, with initial population-level reports emerging in early October 1937 shortly after distribution began. Shipments of the product commenced around September 25, 1937, totaling 240 gallons across 633 consignments to physicians and pharmacies nationwide, often prescribed for infections like strep throat in children and adults. Symptoms typically onset 1 to 3 days post-administration, beginning with nonspecific gastrointestinal distress such as nausea, vomiting, and abdominal pain, progressing to oliguria or anuria as renal function failed, followed by coma and death within 3 to 10 days in fatal cases.^[6]^[20] The first concentrated cluster of illnesses and deaths occurred in Tulsa, Oklahoma, where local physicians, including Dr. Irving H. Calhoun, administered the elixir to multiple pediatric patients starting in early October. By October 10, 1937, affected individuals exhibited severe renal symptoms, with at least six fatalities confirmed by October 11, prompting telegrams from Dr. James Stevenson of the Tulsa County Medical Society and the Springer Clinic to the American Medical Association reporting complete anuria in all cases. These initial victims were predominantly children under 10 years old, who received higher relative doses due to body weight, accelerating the toxic progression; autopsies later revealed oxalate crystals in renal tubules consistent with diethylene glycol metabolism.^[7]^[22] Nationwide recognition accelerated as similar reports surfaced from other states by mid-October, with the American Medical Association issuing warnings on October 16, 1937, after confirming the solvent's role; by then, over a dozen deaths were linked, underscoring the elixir's rapid dissemination and the absence of prior toxicity testing. The swift onset reflected diethylene glycol's pharmacokinetic profile, where peak plasma levels and metabolite accumulation occur within hours, leading to uncorrectable acidosis and uremia without dialysis capabilities at the time.^[17]^[6]

Scale of Mortality and Victim Profiles

The Elixir Sulfanilamide disaster resulted in 107 confirmed deaths between September and October 1937, occurring across 15 states in the United States.^[23] These fatalities stemmed from acute kidney failure induced by diethylene glycol poisoning, with symptoms typically manifesting 7 to 21 days after ingestion, including nausea, vomiting, abdominal pain, and oliguria progressing to anuria.^[16] Of the approximately 353 individuals who received the elixir, the case fatality rate approached 30%, underscoring the solvent's lethality even in therapeutic doses of sulfanilamide.^[24] Victims were predominantly patients prescribed the elixir by physicians for bacterial infections, such as streptococcal sore throats and other conditions treatable by sulfanilamide, particularly those unable to swallow compressed tablets.^[16] A substantial portion—many of whom were children—fit this profile, as the liquid formulation was marketed for pediatric and dysphagic use, with at least 34 pediatric deaths reported among the totals.^[24] Adult victims, numbering around 73, included both men and women, though no disproportionate gender skew is documented; the elixir's distribution targeted general ambulatory care rather than specific demographics beyond age-related swallowing limitations.^[23] Geographic clustering occurred in areas with active shipments, including Oklahoma and other Midwestern and Southern states, reflecting the elixir's rapid dissemination via 633 shipments totaling 240 gallons.^[19]

Investigation and Immediate Aftermath

FDA's Role and Toxicology Findings

The U.S. Food and Drug Administration (FDA), operating under the constraints of the 1906 Pure Food and Drug Act which lacked provisions for pre-market drug safety testing, responded to initial reports of fatalities by launching an urgent investigation in late September 1937.^[25] FDA field agents collected samples from pharmacies, physicians, and victims' families across multiple states, while laboratory chemists analyzed the elixir's composition and conducted toxicity assays.^[3] This effort confirmed that the product contained approximately 10% sulfanilamide dissolved in 72% diethylene glycol (DEG) as the primary solvent, with minor flavoring and coloring additives, and no evidence of bacterial contamination or impurities like mercury.^[26] Toxicological examinations, including post-mortem analyses of at least 76 victims and animal experiments, pinpointed DEG as the causative agent, producing rapid onset of acute kidney failure marked by oliguria or anuria, metabolic acidosis, and degeneration of renal tubules.^[26]^[7] FDA tests on cats and dogs demonstrated that oral doses of DEG equivalent to those in therapeutic amounts of the elixir induced identical renal pathology and lethality within days, with the LD50 estimated at around 1-2 mL/kg body weight, underscoring its unsuspected nephrotoxicity despite prior industrial use.^[3] Sulfanilamide itself was deemed non-toxic at the administered levels, isolating DEG's causal role through controlled comparisons with safe solvents like glycerin.^[26] The investigation revealed no prior safety data on DEG for pharmaceutical applications, as the manufacturer had not performed animal or human toxicity studies, highlighting systemic gaps in oversight that allowed distribution of over 1,100 gallons without federal scrutiny.^[3] FDA documentation attributed 107 deaths—predominantly among children unable to tolerate solid sulfanilamide forms—to cumulative DEG exposure from multiple doses, with autopsy findings consistently showing visceral congestion and renal shutdown absent in uncomplicated sulfanilamide therapy cases.^[25]^[7] These findings, corroborated by independent analyses from the American Medical Association's chemical laboratory, provided empirical evidence that propelled demands for enhanced regulatory authority.^[7]

Product Recall and Public Response

Following confirmation of the toxic effects by the U.S. Food and Drug Administration (FDA) on October 14, 1937, S.E. Massengill Company issued a voluntary recall of Elixir Sulfanilamide, notifying over 1,000 physicians via telegram to return all remaining stock to the company or local health authorities. The FDA, lacking statutory recall authority at the time, coordinated with Massengill and state officials to trace the 240 gallons (approximately 900 liters) shipped primarily to pharmacies and doctors in 15 states from Virginia to California, ultimately recovering about 99% of the distributed product and preventing additional immediate exposures.^[27] Public response was marked by widespread horror and indignation, intensified by the deaths of at least 107 individuals—many of them children under 10 years old treated for routine infections like sore throats—who suffered agonizing renal failure from diethylene glycol poisoning.^[3] Newspapers across the United States sensationalized the crisis with headlines detailing gruesome symptoms such as convulsions, coma, and rapid deterioration, framing it as a preventable corporate negligence that exposed vulnerabilities in drug safety absent pre-market testing requirements.^[27] Initial statements from Massengill president Harold Watkins, asserting the product was "first-class" with "no error in manufacture" despite the fatalities, drew sharp criticism for appearing dismissive, further eroding trust in the pharmaceutical industry and galvanizing demands for federal oversight. The tragedy prompted immediate congressional inquiries and hearings, with public testimony from grieving families and medical experts underscoring the causal link between inadequate solvent toxicity testing and the mass poisoning, thereby catalyzing support for enhanced regulatory powers.^[3]^[28] This outcry reflected a broader societal recognition that empirical safety validation, rather than mere manufacturing claims, was essential to avert such causal chains of harm from unverified formulations.

Regulatory and Legal Repercussions

Criminal Proceedings Against Massengill

The S. E. Massengill Company faced criminal charges under the Federal Food and Drugs Act of 1906 for adulteration and misbranding of Elixir Sulfanilamide, as the product contained diethylene glycol—a poisonous added substance that rendered it injurious to health—and was falsely labeled as an "elixir," a term reserved for alcohol-based preparations under pharmacopeial standards.^[29]^[30] The U.S. Department of Justice initiated proceedings in the Eastern District Court of Tennessee, where company president Samuel Evans Massengill entered a plea of guilty to multiple counts, including at least 174 violations related to the interstate shipment of the misbranded and adulterated drug.^[31] Prosecutors could not pursue charges for manslaughter or negligence causing death, as the 1906 Act lacked provisions requiring pre-market safety testing or holding manufacturers liable for untested formulations' toxicity, limiting enforcement to labeling and purity issues.^[30] Massengill maintained that no laws had been violated beyond technical mislabeling and denied broader liability for the deaths, attributing the disaster to unforeseen solvent effects rather than deliberate misconduct.^[32] The court imposed fines totaling approximately $16,800 in one reported proceeding, though specific judgments like case 29752 documented a $9,300 penalty for adulteration and misbranding.^[30]^[29] No individual executives, including chief chemist Harold Watkins, faced personal criminal prosecution, as liability centered on the corporate entity under the prevailing statute.^[33] These proceedings underscored the inadequacies of existing law, which treated the fatal product as merely mislabeled rather than lethally unsafe, prompting calls for reform but yielding only nominal penalties relative to the 107 confirmed deaths.^[16] Parallel civil lawsuits by victims' families resulted in over $150,000 in settlements, but the criminal case concluded without further escalation.^[30]

Passage of the 1938 Federal Food, Drug, and Cosmetic Act

The Elixir Sulfanilamide disaster, which claimed 107 lives in 1937 primarily due to renal toxicity from the untested solvent diethylene glycol, exposed critical deficiencies in existing U.S. drug regulation under the 1906 Pure Food and Drug Act. That earlier law focused on preventing adulteration and misbranding but imposed no requirement for manufacturers to demonstrate a drug's safety before marketing, enabling S.E. Massengill Co. to distribute the elixir nationwide without toxicity screening. The ensuing public horror, amplified by media reports and FDA investigations confirming the solvent's lethality in animal tests, ignited demands for reform, transforming a moribund legislative proposal into an urgent priority.^[34]^[6]^[5] Efforts to enact comprehensive food, drug, and cosmetic legislation had stalled in Congress for over five years amid resistance from industry groups wary of expanded federal oversight. The sulfanilamide deaths, however, shifted the debate during fall 1937 hearings, where testimony underscored the human cost of absent safety mandates and bolstered advocacy from consumer advocates and journalists. This momentum facilitated passage of the revised bill, with the Senate approving it after amendments and the House following suit, culminating in President Franklin D. Roosevelt's signature on June 25, 1938.^[34]^[5]^[35] The 1938 Federal Food, Drug, and Cosmetic Act fundamentally altered pharmaceutical regulation by requiring manufacturers to file a New Drug Application with the FDA, furnishing evidence from "adequate and well-controlled investigations" proving a new drug's safety for its intended use before interstate commerce. The FDA gained authority to review these applications within 60 days, approving only those meeting safety standards or deeming them safe by default if no objection was raised; failure to comply invited seizure and injunctions. Labels were mandated to include directions for safe use under lay conditions, while the Act prohibited misbranding via unsubstantiated efficacy claims, directly remedying the elixir's unchecked dissemination and establishing pre-market safety as a federal prerequisite—though it deferred requirements for efficacy until 1962 amendments.^[34]^[6]^[35]

Scientific and Toxicological Insights

Mechanism of Diethylene Glycol Poisoning

Diethylene glycol (DEG) exerts its toxicity primarily through hepatic metabolism following gastrointestinal absorption, where it is rapidly taken up and oxidized by alcohol dehydrogenase to form 2-hydroxyethoxyacetaldehyde, which is further metabolized by aldehyde dehydrogenase to 2-hydroxyethoxyacetic acid (2-HEAA).^[36] A parallel pathway involves omega-oxidation of DEG to produce diglycolic acid (DGA), identified as the principal nephrotoxic metabolite responsible for acute kidney injury.^[37] Unlike ethylene glycol, whose toxicity stems from glycolic acid-induced acidosis, DEG's renal damage is driven by DGA accumulation in proximal tubules, leading to selective necrosis without significant contribution from 2-HEAA.^[36]^[38] DGA induces mitochondrial dysfunction by chelating intracellular calcium, thereby reducing substrate availability and impairing oxidative phosphorylation, which elevates reactive oxygen species and triggers cellular apoptosis in renal cells.^[39] This results in proximal tubular injury characterized by vacuolization, loss of brush border, and cast formation, culminating in oliguric renal failure and metabolic acidosis from impaired bicarbonate reabsorption.^[40] Experimental rodent models demonstrate dose-dependent thresholds for these effects, with DGA concentrations correlating directly to histopathologic kidney damage, including elevated serum creatinine and urea nitrogen levels.^[41] Neurological manifestations, such as peripheral neuropathy and cranial nerve palsies observed in survivors, arise from metabolite-mediated axonal degeneration, potentially involving 2-HEAA's interference with myelin synthesis or DGA's extension of toxicity beyond kidneys via systemic distribution.^[42] Hepatotoxicity occurs less prominently, linked to transient enzyme elevations from oxidative stress, but does not typically progress to failure.^[40] Inhibition of DEG metabolism with ethanol or fomepizole prevents target organ toxicity, underscoring the causal role of these metabolites over the parent compound.^[38] While the full molecular pathways remain incompletely elucidated, clinical poisonings consistently feature delayed onset (24-72 hours post-ingestion) due to metabolite buildup, distinguishing DEG from direct-acting toxins.^[43]

Comparative Analysis with Other Solvents

Diethylene glycol (DEG) was selected for Elixir Sulfanilamide primarily for its effective dissolution of sulfanilamide, which has low aqueous solubility of 0.75 g/100 mL at 25°C, enabling a concentrated 10% formulation with 72% DEG and 16% water that appeared clear, viscous, and raspberry-flavored for palatability.^[44]^[4] This contrasted with traditional solvents like ethanol, where sulfanilamide solubility remains moderate (approximately 1.7 g/100 mL), insufficient for high-dose liquid delivery without excessive volume or additional co-solvents.^[45] Safer alternatives, such as propylene glycol (PG) and glycerol, offered comparable solvency but were evidently not prioritized. PG, in binary mixtures with water, markedly increases sulfanilamide solubility proportional to its concentration, with experimental data at 293–313 K demonstrating enhanced dissolution suitable for pharmaceutical elixirs.^[46] Glycerol similarly solubilizes sulfanilamide effectively, though its greater viscosity could complicate dosing and mouthfeel compared to DEG's syrup-like consistency.^[47] Ethanol, while viable, poses challenges for pediatric formulations due to its odor, potential for rapid absorption, and regulatory preferences for non-alcoholic vehicles in 1937.^[48] Toxicity assessments reveal DEG's profound risks absent in these substitutes. DEG ingestion leads to metabolism into nephrotoxic and neurotoxic compounds like diglycolic acid, causing renal tubular necrosis and fatalities at cumulative doses of 1–2 mL/kg in vulnerable populations, as confirmed by post-1937 toxicological analyses.^[49] PG, conversely, exhibits minimal acute toxicity (oral LD50 >20 g/kg in rats), is classified as generally recognized as safe for oral use, and has not prompted analogous mass poisonings when employed as a solvent.^[50] Glycerol demonstrates even lower risk, with oral LD50 exceeding 12 g/kg and routine incorporation in oral medicinals without systemic poisoning reports.^[51] DEG's selection, despite these options, prioritized formulation aesthetics and economics over preclinical safety testing, highlighting a critical lapse in evaluating solvent biocompatibility.^[52]

Long-Term Impact and Lessons

Evolution of Pre-Market Drug Safety Testing

The Elixir Sulfanilamide disaster of 1937 underscored the absence of mandatory pre-market safety testing under the 1906 Pure Food and Drug Act, which addressed only adulteration and misbranding without requiring proof of drug safety prior to interstate distribution.^[52] Manufacturers like S.E. Massengill Company could formulate and market liquid sulfanilamide using untested diethylene glycol as a solvent, leading to 107 confirmed deaths from renal failure, as no federal law compelled toxicity assessments in animals or humans.^[4] This regulatory void prompted congressional hearings revealing widespread industry practices of minimal or no preclinical evaluation, galvanizing public and legislative demand for reform.^[53] Enacted on June 25, 1938, the Federal Food, Drug, and Cosmetic (FD&C) Act introduced the first U.S. requirement for pre-market demonstration of drug safety, mandating that manufacturers file New Drug Applications (NDAs) with evidence from "adequate and well-controlled" investigations, typically including animal toxicity studies and limited human trials, before interstate marketing.^[25] The FDA gained authority to review and approve NDAs based on submitted data, rejecting applications for drugs deemed unsafe, a direct response to the sulfanilamide incident where post-hoc toxicology confirmed diethylene glycol's lethality in animal models after human casualties.^[54] Initial implementation emphasized solvent and formulation safety, with early regulations in the 1940s specifying acute and chronic animal dosing studies to predict human risks, though human data remained observational due to ethical constraints.^[55] Post-1938 evolution formalized phased testing protocols: by the 1950s, FDA guidelines required sequential preclinical animal studies (e.g., rodents and non-rodents for organ-specific toxicity) before Investigational New Drug (IND) exemptions for human trials, evolving into the modern structure with Phase I focusing on safety in small cohorts, Phase II on dosing and preliminary safety, and Phase III on confirmatory large-scale safety alongside efficacy.^[55] The 1962 Kefauver-Harris Amendments built on this by mandating "adequate and well-controlled" clinical investigations for safety claims, informed consent, and Institutional Review Boards, addressing gaps exposed in tragedies like thalidomide while reinforcing pre-1938 lessons on solvent toxicity.^[25] These advancements shifted from reactive post-market responses to proactive, evidence-based pre-approval scrutiny, reducing but not eliminating risks, as evidenced by ongoing refinements in Good Laboratory Practices (1978) and International Conference on Harmonisation guidelines for standardized toxicity testing.^[4]

Influence on Pharmaceutical Industry Practices

The Elixir Sulfanilamide disaster of 1937, which resulted in 107 deaths from diethylene glycol toxicity, exposed fundamental flaws in pharmaceutical formulation practices, particularly the lack of toxicity testing for solvents and vehicles beyond active ingredients. Prior to the incident, manufacturers like S.E. Massengill prioritized rapid market entry and palatability, dissolving sulfanilamide in untested industrial-grade diethylene glycol without animal or human safety trials for the complete elixir, assuming the solvent's prior use in unrelated products indicated harmlessness.^[16]^[6] This oversight shifted industry norms toward mandatory preclinical toxicity testing of entire drug products, including excipients, using animal models to detect renal and hepatic damage akin to that observed in the disaster.^[4]^[56] Pharmaceutical firms responded by revising solvent selection protocols, abandoning unvetted industrial alternatives in favor of pharmacologically evaluated options like glycerin or ethanol, which required empirical validation of biocompatibility before incorporation.^[6] The event catalyzed internal quality assurance measures, such as batch-specific purity assays and stability testing under physiological conditions, to preempt formulation-induced toxicities, reducing reliance on anecdotal evidence for excipient safety.^[57] By 1938, leading companies had begun voluntary adoption of these standards to avert litigation and recalls, establishing a precedent for integrating toxicological data into early-stage development pipelines.^[4] Longer-term, the disaster influenced manufacturing ethics and risk management, prompting industry-wide recognition that efficacy alone does not suffice without causal verification of non-toxicity across dosage forms. This led to enhanced documentation of formulation rationales and solvent sourcing, minimizing adulteration risks from impure suppliers, as evidenced by subsequent reductions in solvent-related adverse events reported in pharmacovigilance records.^[20]^[6] The incident's empirical lessons—demonstrating how vehicle toxicity can overwhelm therapeutic benefits—embedded precautionary testing into corporate R&D frameworks, fostering a culture of empirical validation over expediency.^[3]

Contemporary Relevance and Case Studies

The Elixir Sulfanilamide incident exemplifies persistent vulnerabilities in pharmaceutical manufacturing, particularly regarding untested excipients like diethylene glycol (DEG), which has caused recurrent mass poisonings despite regulatory reforms. Recent outbreaks demonstrate that while pre-market safety testing became mandatory in the U.S. following 1937, inadequate oversight in global supply chains—often involving substitution of cheap industrial solvents for pharmaceutical-grade ones—continues to endanger vulnerable populations, especially children consuming liquid formulations. These events underscore the causal link between skipped toxicity assays and acute kidney injury, metabolic acidosis, and death, echoing the original disaster's mechanism.^[58]^[59] A prominent case study is the 2022 Gambia outbreak, where 78 children aged under five developed acute kidney injury after ingesting four substandard cough and cold syrups manufactured by India's Maiden Pharmaceuticals; laboratory analysis confirmed DEG contamination at levels up to 38.6%, with over 80% fatality among anuric cases, totaling approximately 66-70 deaths as estimated by health authorities. The World Health Organization issued a global alert on October 5, 2022, urging recalls and highlighting falsified excipient certificates from suppliers. Investigations revealed regulatory gaps in export certification and post-market surveillance, prompting international scrutiny of Indian generic producers.^[60]^[59]^[61] Similar patterns emerged in Uzbekistan in 2023, with 18 child deaths attributed to DEG in Indian-exported syrups, and in Indonesia, where elevated acute kidney injury cases among children correlated with contaminated antihistamine and cough syrups from the same supply networks. In October 2025, at least 20-23 children in India's Madhya Pradesh state succumbed after consuming domestic cough syrups like Coldrif, tainted with DEG concentrations nearing 45%, leading to WHO alerts on October 13 for three implicated products and exposing ongoing domestic enforcement lapses. These incidents, totaling hundreds of pediatric fatalities since 2022, affirm DEG's role as a preventable toxin when manufacturers bypass solvent purity verification, reinforcing calls for harmonized global testing protocols beyond U.S. standards.^[62]^[63]^[64]

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Dec 12, 2017 · In 1936, Colebrook began testing sulfanilamide as an antibacterial treatment of puerperal fever with his first assistant, Anthoney W. Purdie.
[13]
[PDF] Modern Medicine and the 20th Century Decline in Mortality
This paper studies the contribution of sulfa drugs, a groundbreaking medical innovation in the 1930s, to declines in U.S. mortality. For several often-fatal ...<|control11|><|separator|>
[14]
Drugs That Changed Society: History and Current Status of the Early ...
Oct 7, 2021 · In 1938, May and Baker marketed 4-sulfapyridine (6) as the first sulfa drug, which could cure “captain of the death“ bacterial pneumonia. In ...
[15]
Sulfonamide drugs: structure, antibacterial property, toxicity, and ...
The purpose of this review was to examine SN drug structure, function, and toxicity in treated human and animal patients as well as the environment.
[16]
None
### Summary of Therapeutic Applications and Efficacy of Sulfanilamide Prior to the Elixir Incident
[17]
Special Article - JAMA Network
tent of diethylene glycol. Sulfanilamide is the name of one of a group of closely related chemicals first reported in European medical ...
[18]
Toxicity of Sulfanilamide and Diethylene Glycol
This elixir contained 40 grains of sulfanilamide per ounce of a solvent containing 72% diethylene glycol by volume.Missing: manufacturing | Show results with:manufacturing<|separator|>
[19]
The Accidental Poison That Founded the Modern FDA - The Atlantic
Jan 16, 2018 · Elixir Sulfanilamide was a breakthrough antibiotic—until it killed more than 100 people. An Object Lesson.
[20]
Elixir Sulfanilamide - an overview | ScienceDirect Topics
The Elixir Sulfanilamide disaster of 1937 was one of the most consequential mass poisonings of the 20th century.
[21]
Sulfanilamide Disaster | FDA
Jan 31, 2018 · In June 1937, however, a salesman for the S.E. Massengill Co., in Bristol, Tenn., reported a demand in the southern states for the drug in ...
[22]
SULFANILAMIDE - JAMA Network
BRISTOL, TENN.-VA. Label of gallon bottle of Elixir of Sulfanilamide-Massengill. The presence of diethylene glycol was.
[23]
[PDF] Milestones of Drug Regulation in the United States - FDA
Jun 30, 2025 · 1937 Elixir Sulfanilamide, containing the poisonous solvent diethylene glycol, kills 107 persons, many of whom are children, dramatizing the ...Missing: exact | Show results with:exact
[24]
[PDF] OPINION ON Diethylene glycol - European Commission
Jun 24, 2008 · 353 patients received Elixir Sulfanilamide during a 4-week period in the fall of 1937. There were 105 deaths (34 children and 71 adults) and 248 ...
[25]
Milestones in US Food and Drug Law - FDA
Jan 30, 2023 · 1937. Elixir of Sulfanilamide, containing the poisonous solvent diethylene glycol, kills 107 persons, many of whom are children, dramatizing the ...<|control11|><|separator|>
[26]
PATHOLOGIC EFFECTS OF ELIXIR OF SULFANILAMIDE ...
During the months of September and October 1937 at least seventy-six1 human beings in various localities died as a result of poisoning by Elixir of.Missing: formulation | Show results with:formulation
[27]
Wallace Reveals How Federal Agents Traced Elixir to Halt Fatalities
A graphic story of a race against death from “elixir sulfanilamide,” carried on by the Food and Drug Administration in fifteen States from Virginia to ...Missing: toll | Show results with:toll
[28]
Why the Watchdog Won't Bite: U.S. Food and Drug Administration ...
Nov 4, 2016 · The so-called “Massengill massacre” in 1937 caused deaths in more than 100 patients who took “elixir sulfanilamide,” which had used the ...
[29]
https://fdanj.nlm.nih.gov/?f%5Bfdanj.caseissuedate%5D%5B%5D=March%2B1939&f%5Bfdanj.title%5D%5B%5D=29752.%2BAdulteration%2Band%2Bmisbranding%2Bof%2BElixir%2BSulfanilamide.%2BU.%2BS.%2Bv.%2BSamuel%2BEvans%2BMassengill%2B%2528S.%2BE.%2BMassengill%2BCo.%2529.%2BPlea%2Bof%2Bguilty.%2BFine.%2B%25249%252C300.&per_page=10&sort=fdanj.title%2Bdesc
[30]
Medicine: Massengill Pays | TIME
Prosecution by the Government, however, was limited to minor charges under the old 1906 Pure Food & Drug Act. Last week, in Eastern District Court of Tennes see ...Missing: criminal proceedings
[31]
Elixir sulfanilamide scandal | Research Starters - EBSCO
The Elixir sulfanilamide scandal, which unfolded in the late 1930s, represents a significant event in the history of pharmaceutical regulation in the United ...Missing: incident | Show results with:incident
[32]
Prescription Elixir Causes More than One Hundred Deaths - EBSCO
In 1937, a pharmaceutical company named S. E. Massengill introduced a new liquid form of the antibiotic sulfanilamide, marketed as elixir sulfanilamide.
[33]
Special Article - JAMA Network
1935. For some time before putting "Elixir Sulfanilamide" on the market, the S. E. Massengill Company had been.
[34]
Part II: 1938, Food, Drug, Cosmetic Act - FDA
Nov 27, 2018 · However, the solvent in this untested product was a highly toxic chemical analogue of antifreeze; over 100 people died, many of whom were ...Missing: exact | Show results with:exact
[35]
1938 Food, Drug, and Cosmetic Act (FDCA) - US Pharmacopeia (USP)
Containing an untested solvent, diethylene glycol (DEG), similar to anti-freeze, the elixir caused 107 deaths. To prevent similar disasters, Congress crafted ...
[36]
Diglycolic acid is the nephrotoxic metabolite in diethylene glycol ...
DEG is metabolized to two primary metabolites, 2-hydroxyethoxyacetic acid (2-HEAA) and diglycolic acid (DGA), which are believed to be the proximate toxicants.
[37]
Diglycolic Acid Is the Nephrotoxic Metabolite in Diethylene Glycol ...
The majority of literature examining DEG poisonings has suggested that 2-HEAA is the likely toxic metabolite responsible for DEG toxicity with no mention of any ...Abstract · MATERIALS AND METHODS · RESULTS · DISCUSSION
[38]
Inhibition of Metabolism of Diethylene Glycol Prevents Target Organ ...
The mechanism of its toxicity has not been defined as to the precise relationship between the metabolism of DEG and target organ toxicity.
[39]
Diglycolic acid, the toxic metabolite of diethylene glycol, chelates ...
These results indicate that DGA produces mitochondrial dysfunction by chelating calcium to decrease the availability of substrates and of reducing ...
[40]
Diethylene glycol-induced toxicities show marked threshold dose ...
DEG poisoning clinically manifests in metabolic acidosis, hepatotoxicity, renal failure, and peripheral neuropathy, with the hallmark being acute renal failure ...
[41]
Role of Tissue Metabolite Accumulation in the Renal Toxicity of ...
Jul 29, 2011 · DEG produces toxicity because of its metabolism, although the mechanism of its toxicity has not been further defined.
[42]
Diethylene glycol produces nephrotoxic and neurotoxic effects in ...
DEG poisonings are characterized by acute kidney injury (AKI) and by neurological sequelae such as decreased reflexes or face and limb weakness.
[43]
Diethylene glycol poisoning - PubMed
Aim: The aim of this review is to summarize all main aspects of DEG poisoning including epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, ...
[44]
Sulfanilamide | C6H8N2O2S | CID 5333 - PubChem - NIH
3.2.4 Solubility ; Burnham Center for Chemical Genomics. 0.1 to 1.0 mg/mL at 72 °F (NTP, 1992) ; CAMEO Chemicals. 7500 mg/L (at 25 °C) ; DrugBank. IN WATER: 7.5 G/ ...
[45]
Sulfanilamide Datasheet - Selleck Chemicals
Molecular Weight, 172.2, CAS No. 63-74-1 ; Solubility (25°C)*, In vitro, DMSO, 34 mg/mL (197.44 mM) ; Solubility (25°C)*, In vitro · Ethanol, 17 mg/mL (98.72 mM).
[46]
Thermodynamics of Sulfanilamide solubility in Propylene Glycol + ...
Aug 6, 2025 · The solubility of sulfanilamide (SA) in propylene glycol + water cosolvent mixtures was determined at temperatures from 293.15 to 313.15 K.Missing: glycerin | Show results with:glycerin
[47]
Sulfanilamide - Sciencemadness Wiki
Jul 31, 2023 · 0.75 g/100 ml (25 °C) 47.7 g/100 ml (100 °C). Solubility, Soluble in aq. alkali, ethanol, glycerol, hydrochloric acid, propylene glycol
[48]
Sulfanilamide, 98% - Thermo Scientific Chemicals
Soluble in water, acetone, ethanol, glycerol, propylene glycol and hydrochloric acid. Insoluble in chloroform, ether, benzene and petroleum ether.
[49]
DEATHS FOLLOWING ELIXIR OF SULFANILAMIDE-MASSENGILL
Nine out of ten patients who had been given a proprietary elixir of sulfanilamide died recently in Tulsa, Okla., from anuria which apparently resulted directly ...
[50]
A comparative analysis of Diethylene Glycol versus other glycols in ...
Jul 8, 2025 · While not as strong a solvent as EG or DEG, its low toxicity and compatibility with biological systems make it ideal for sensitive applications.
[51]
[PDF] Guidance for Industry: Testing of Glycerin for Diethylene Glycol - FDA
In 1937, an outbreak of DEG poisoning occurred in the United States, which resulted from people ingesting elixir of sulfanilamide that contained DEG as a ...
[52]
[PDF] Sulfanilamide Disaster - FDA
The medicine that killed Dr. Calhoun's patients was Elixir Sulfanilamide. During September and. October 1937 this drug was responsible for the deaths of more ...
[53]
Therapeutic disasters that hastened safety testing of new drugs
New drugs were not required to undergo premarket safety testing in the United States until 1938, when a therapeutic disaster-the Elixir Sulfanilamide tragedy- ...
[54]
Food, Drug, and Cosmetic Act - StatPearls - NCBI Bookshelf
On June 25th, 1938, President Franklin D. Roosevelt signed the FDCA into law, marking a milestone for modern-day consumer protections. The FDCA and its ...
[55]
[PDF] FDA and Clinical Drug Trials: A Short History
A new and key provision in the 1962 amendments was the requirement that, in addition to the pre-market demonstrations of safety already required under the 1938 ...
[56]
Elixir Sulfanilamide - an overview | ScienceDirect Topics
This disaster prompted the enactment of the 1938 Federal Food, Drug and Cosmetic Act, which mandated safety proof for new drugs. AI generated definition based ...
[57]
The origins of robust pharmaceutical quality: Elixir Sulfanilamide
The Elixir Sulfanilamide disaster was a tragic event that occurred in 1937, resulting in the deaths of over 100 people, many of them children.
[58]
Medication-Associated Diethylene Glycol Mass Poisoning — A Preventable Cause of Illness and Death | NEJM
### Summary of Diethylene Glycol Mass Poisonings
[59]
Catastrophic Diethylene Glycol Poisoning in Children - PMC - NIH
The adverse clinical manifestations of DEG result from the formation of the metabolite diglycolic acid (DGA). This toxic metabolite is speculated to cause the ...Missing: mechanism | Show results with:mechanism
[60]
Medical Product Alert N°6/2022: Substandard (contaminated ...
Oct 5, 2022 · This WHO Medical Product Alert refers to four substandard products, identified in The Gambia and reported to WHO in September 2022.
[61]
Acute Kidney Injury Among Children Likely Associated with - CDC
Mar 3, 2023 · Diethylene glycol (DEG)–contaminated medications present a global health threat, especially in low-income countries. What is added by this ...
[62]
Gambian children's deaths due to contaminated cough syrups are a ...
The WHO estimates that ∼66 children in The Gambia passed away after ingesting a cough syrup that was possibly connected with acute kidney damage due to toxic ...
[63]
WHO flags regulation gaps after India child deaths from cough syrups
Oct 10, 2025 · At least 20 children have died after consuming cough syrups contaminated with diethylene glycol.
[64]
WHO raises alert over DEG-contaminated cough syrups in India
Oct 13, 2025 · The World Health Organization (WHO) issued an alert on Monday identifying oral cough syrups manufactured in India that contain diethylene ...