Eleventh Triennial Toxicology Salary Survey.

This is the eleventh in a series of salary surveys for toxicologists conducted at three-year intervals that began in 1988. Previous salary surveys were conducted in 1988, 1991, 1995, 1998, 2001, 2004, 2007 (which was posted electronically, but not published), 2012, 2016 and 2020. In addition to presenting the 2022 results, herein we are providing additional data and an analysis of the trends for employment and pay in toxicology over the last 35 years. The eleventh Triennial Toxicology Salary Survey was conducted as a joint project by the American College of Toxicology (ACT) and the Society of Toxicology (SOT). In addition to the two parent organizations, eight others (the Society for Birth Defects Research, the Society of Toxicologic Pathology, the Safety Pharmacology Society, the American Board of Toxicology (ABT), the Academy of Toxicological Sciences, the Roundtable of Toxicology Consultants, the Society of Environmental Toxicology and Chemistry (SETAC), and the Environmental Mutagenesis and Genomics Society) supported the effort by distributing the Survey Monkey-based instrument to their memberships. Surveys were not distributed to regional SOT chapters, causing there to be minimal responses below the doctorate and master's degree levels. It should be noted that there continues to be a significant increase in the number of individuals reporting six-figure incomes and in those receiving significant sums as bonuses.

Skin sensitization in silico protocol.

The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducting a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization.

Tenth Triennial Toxicology Salary Survey.

This survey serves as the tenth in a series of toxicology salary surveys conducted at 3-year intervals and beginning in 1988. An electronic survey instrument was distributed to members of the Society of Toxicology, American College of Toxicology, and 8 additional professional organizations. Question items inquired about gender, age, degree, years of experience, certifications held, areas of specialization, society membership, employment and income. Overall, 1338 responses were received. The results of the toxicology salary survey provide insight into the job market and career path for current and future toxicologists.

Nonclinical Safety and Toxicokinetics of MnTE-2-PyP (BMX-010), a Topical Agent in Phase 2 Trials for Psoriasis and Atopic Dermatitis.

Since our earlier publication (Gad et al, 2013), BioMimetix has advanced BMX-010 (Manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin or MnTE020PyP; CASRN 219818-60-7) into clinical development as a topical agent for the treatment of psoriasis, atopic dermatitis, and pruritus (idiopathic nonspecific itch). A multiple dose phase I study has been completed in 64 patients without any serious adverse effects. During the course of development, the formulation was initially a gel but has been modified to a cream formulation. The nonclinical safety program has been carried onward to assess preclinical risk to patients. Additional studies completed and reported here include dermal sensitization in a Guinea Pig maximization test study, 2 rabbit phototoxicity studies, a 28-day oral toxicity study in juvenile mice, a 28-day topical systemic toxicity study in Gottingen minipigs, range-finding studies, and complete embryo-fetal developmental toxicity (Segment II) studies in mice and rabbits, an ICH M7 compliant qualification of impurities using 2 (Q)SAR in silico methods, and a 14-day subcutaneous toxicity study of mice to qualify an impurity. All studies (except the (Q)SAR evaluations) were performed in accordance with Good Laboratory Practices (GLP) using Good Manufacturing Practices (GMP) drug substance. The systemic toxicity studies, with the exception of the juvenile toxicity study, included toxicokinetic evaluations, which are reported here. The phase I clinical study had 67 patient participants who received topically applied BMX-010, and there were no notable safety findings and included pharmacokinetic determinations on these patients which are also reported here. Chronic GLP toxicity studies have been initiated in the mouse (6-month oral) and minipig (9-month dermal). To date, the only observed nonclinical toxicity remains a reversible hypertension seen in mice in response to Cmax levels with a no effect threshold, and there have been no drug-related adverse effects.

Toxicologic Pathology Forum Opinion Paper: Considerations for Toxicologic Pathologists Evaluating the Safety of Biomaterials and Finished Medical Devices.

Safety ("biocompatibility") assessment of medical devices has evolved along a different path than that of drugs, being historically governed more by the considerations and needs of engineers rather than chemists and biologists. As a result, the involvement of veterinary pathologists has been much more limited-almost entirely to evaluating tissue responses in tissues in direct contact with implanted devices. As devices have become more complex in composition, structure, placement, and use, concerns as to adverse systemic responses in patients have called for more comprehensive and thoughtful evaluations of effects throughout the body. Further complexities arise from the increasing marriage of devices and drug/biologic therapeutics to achieve either better dose control and, specifically, in delivery to target organs/tissues or better tolerance of the body to medical devices (i.e., minimization of the foreign body response). The challenge to pathologists is to integrate in new technologies (such as in vivo imaging and immunology) and ways of viewing interactions with patient bodies. To fail to do so will allow the methods and standards for medical device safety evaluation to be based on chemical analysis and then the limited details inherent in literature-based risk assessments.

Proceedings of the 2017 National Toxicology Program Satellite Symposium.

The 2017 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri," was held in Montreal, Quebec, Canada at the Society of Toxicologic Pathology's 36th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and other topics covered during the symposium included renal papillary degeneration in perinatally exposed animals, an atriocaval mesothelioma, an unusual presentation of an alveolar-bronchiolar carcinoma, a paraganglioma of the organ of Zuckerkandl (also called an extra-adrenal pheochromocytoma), the use of human muscle samples to illustrate the challenges of manual scoring of fluorescent staining, intertubular spermatocytic seminomas, medical device pathology assessment and discussion of the approval process, collagen-induced arthritis, incisor denticles, ameloblast degeneration and poorly mineralized enamel matrix, connective tissue paragangliomas, microcystin-LR toxicity, perivascular mast cells in the forebrain thalamus unrelated to treatment, and 2 cases that provided a review of the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) bone nomenclature and recommended application of the terminology in routine nonclinical toxicity studies.

Initial Evaluation of the Safety of Nanoshell-Directed Photothermal Therapy in the Treatment of Prostate Disease.

To evaluate the clinical safety profile for the use of gold nanoshells in patients with human prostate cancer. This follows on the nonclinical safety assessment of the AuroShell particles reported previously. Twenty-two patients, with biopsy diagnosed prostate cancer, underwent nanoshell infusion and subsequent radical prostatectomy (RRP). Fifteen of these patients had prostates that were additionally irradiated by a single-fiber laser ablation in each prostate hemisphere prior to RRP. Patients in the study were assessed at 9 time points through 6 months postinfusion. Adverse events were recorded as reported by the patients and from clinical observation. Blood and urine samples were collected at each patient visit and subjected to chemical (16 tests), hematological (23 tests), immunological (3 tests, including total PSA), and urinalysis (8 tests) evaluation. Temperature of the anterior rectal wall at the level of the prostate was measured. The study, recorded 2 adverse events that were judged attributable to the nanoparticle infusion: (1) an allergic reaction resulting in itching, which resolved with intravenous antihistamines, and (2) in a separate patient, a transient burning sensation in the epigastrium. blood/hematology/urinalysis assays indicated no device-related changes. No change in temperature of the anterior rectal wall was recorded in any of the patients. The clinical safety profile of AuroShell particles is excellent, matching nonclinical findings. A recent consensus statement suggested that the published literature does not support a preference for any ablation technique over another.(1) Now that clinical safety has been confirmed, treatment efficacy of the combined infusion plus laser ablation in prostate will be evaluated in future studies using imaging modalities directing the laser against identified prostate tumors.

Miniature Swine Breeds in Toxicology and Drug Safety Assessments: What to Expect during Clinical and Pathology Evaluations.

The use of miniature swine as a nonrodent species in safety assessment has continued to expand for over a decade, and they are becoming routinely used in toxicology and in pharmacology as well as a model for human diseases. Miniature swine models are regularly used for regulatory toxicity studies designed to assess safety of new therapeutic compounds given through different routes of exposure and are used as an alternative model to the canine or the nonhuman primate. Translational preclinical swine study data presented support the current finding that miniature swine are the animal model of choice for assessment of drug absorption, tolerance, and systemic toxicity following systemic exposures. Because research investigators need to be familiar with important anatomic and histopathologic features of the miniature swine in order to place toxicopathologic findings in their proper perspective, clinical and anatomic pathology data from a large number of Sinclair, Hanford, Yucatan, and Göttingen breeds from control groups from a wide variety of studies performed between 2004 and 2014 will be presented, compared, and partially illustrated.

Nonclinical Safety Assessment of PER977: A Small Molecule Reversal Agent for New Oral Anticoagulants and Heparins.

A new molecular entity, PER977 (di-arginine piperazine), is in clinical development as an anticoagulant reversal agent for new oral anticoagulants and heparins. The good laboratory practices (GLP)-compliant studies were conducted to evaluate the toxicity of PER977 and its primary metabolite, 1,4-bis(3-aminopropyl)piperazine (BAP). PER977 and BAP were negative for systemic toxicity in dogs and rats. PER977 was rapidly eliminated from the blood with little to no accumulation. PER977 was negative for genotoxicity and did not alter neurological, respiratory, or cardiovascular function. Maximum tolerated doses for PER977 were 40 (rat) and 35 mg/kg (dog), and greater than 80 mg/kg (rat) for BAP. The no observable adverse effect level (NOAEL) for 14-day intravenous exposure to both rats and dogs was 20 mg/kg/d. For BAP, the NOAELs for 14-day intravenous exposure to rats and dogs were 5 and 20 mg/kg, respectively. Based on these results, a safe and conservative dose level of 19.4 mg/d was used for the PER977 first in human study.

Safety assessment of EPA-rich polar lipid oil produced from the microalgae Nannochloropsis oculata.

Almega PL is an eicosapentaenoic acid-rich ω-3 oil that is isolated from Nannochloropsis oculata algae and developed as a dietary supplement. The safety of the algal oil was evaluated in 14- and 90-day studies in Sprague-Dawley rats by oral gavage at dose levels of 0, 250, 500, and 2500 mg/kg/d and 0, 200, 400, and 2000 mg/kg/d, respectively. No mortalities occurred and no signs of toxicity were observed during the studies. No treatment-related effects were seen for body weight, food consumption, ophthalmology, neurological effects, urinalysis, clinical pathology, gross pathology, organ weights, or histopathology. Although statistically significant effects were noted for some end points, none were considered to be of toxicological significance. The no observed adverse effect level for Almega PL was 2000 mg/kg/d. Additionally, Almega PL was not mutagenic in Salmonella typhimurium or Escherichia coli, did not induce chromosome aberrations in Chinese hamster ovary cells, and did not induce genotoxic effects in vivo in rat bone marrow erythrocytes.

A review of the nonclinical safety of Transcutol®, a highly purified form of diethylene glycol monoethyl ether (DEGEE) used as a pharmaceutical excipient.

Transcutol® (Diethylene glycol monoethyl ether, DEGEE), CAS # 111-90-0, is commonly used as a vehicle in the formulation or manufacturing process of pharmaceuticals, cosmetics, and food additives. This paper presents unpublished nonclinical safety data using a form of DEGEE which includes a significantly decreased level of impurities, specifically ethylene glycol and diethylene glycol. It also reviews the history of use, regulatory status, and previously published toxicity data for DEGEE. The review supports that DEGEE is well tolerated across animal species and gender with toxicity occurring only at levels well above those intended for human use. At high levels of exposure, the kidney is identified as the critical target organ of DEGEE toxicity. DEGEE is negative for genotoxicity in in vitro and in vivo studies. Subchronic and chronic toxicity studies produced no reports of preneoplastic changes in organs, but the animal data is insufficient to allow a definitive opinion as to carcinogenicity. In silico data suggested that DEGEE is not carcinogenic or genotoxic. Developmental toxicity was seen in rats but only at levels 200 times greater than the estimated oral Permissible Daily Exposure Level of 10 mg/kg/day. The nonclinical data along with the long history of DEGEE use as a vehicle and solvent by multiple routes provide evidence of its safety. Furthermore, the novel data discussed herein provides evidence that toxicity previously associated with high levels of DEGEE in nonclinical studies conducted prior to 1990 could possibly be attributed to the presence of significant amounts of ethylene glycol or other impurities.

Safety and regulatory requirements and challenge for CNS drug development.

As our recognition and understanding of diseases and disorders of the central nervous system (CNS) become more insightful, and society's concerns for the safety, efficacy, and use of such drugs become more acute, the regulatory requirements and expectations around assessing potential safety of the drug have continued to become more complex. Currently, these concerns and requirements are addressed in a time phased manner, attempting to match the advance of spending rate on assessing safety issues in alignment with advancing the moiety through development of the therapeutics. This article seeks to communicate all the critical but frequently overlooked aspects of current and pending regulatory requirements including the lesser known parts associated with impurities, active metabolites, and distribution of active components to (and subsequent clearance from) the population brain. While there are some exciting developments in treating CNS diseases with stem cells and some protein based therapies (Aboody et al., 2011), drugs meant to favorably effect, prevent, or cure a disease process within the central nervous system (CNS) are primarily small molecule and must meet a number of regulatory and scientifically mandated criteria to establish that their safety in clinical use is acceptable. This is initially done in in vivo animals or in in vitro preparations. The starting place for such nonclinical safety assessment requires some fundamental assumptions about the potential therapeutic (Ball et al., 2007; Gad, 2009; ICH S6, 2004; ICH M3 (R2), 2008). The first assumption is that the primary intended route of therapeutic administration is oral, as is indeed the case for the vast majority of both current and for most potential new drugs. Most aspects of nonclinical safety assessment do not depend on route, and we will consider the situations where the use of other routes influences requirements for nonclinical safety assessment, and why. A second general case assumption in the usual case is that drug administration frequency (or regimen) is once daily, though this assumption is less frequently made (in real life) than the oral route assumption. Regulations, costs, and acceptance of risks (Enna and Williams, 2009) along with adherence to the phased process of clinical drug development have caused the task or flow of performances of regulatory nonclinical safety assessment studies to be considered as occurring in three sequential parts (once the initial candidate screening and lead selection phase are complete). These are the studies (1) done to allow initiation of clinical trials, (2) done to allow initiation of clinical trials sufficient to support a marketing application, and (3) required to allow a marketing application. Employment of new technologies, such as in vivo imaging has aided, to both help understand specificity of delivery to target tissue sites and mechanisms of both action and undesirable actions.

A nonclinical safety assessment of MnTE-2-PyP, a manganese porphyrin.

Manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP or BMX-010; CASRN 219818-60-7) is a manganese porphyrin compound developed as a potential drug substance for use as a radioprotective and for the ex vivo treatment of cells, tissues, and organs intended for transplantation. In preparation for an investigational new drug filing, a full good laboratory practice nonclinical safety assessment was conducted in order to evaluate the safety of MnTE-2-PyP and included the performance of in vitro genotoxicity studies, local tissue tolerance evaluation, safety pharmacology core battery studies, and single- and repeat-dose intravenous (iv) toxicity studies in mice and monkeys. The MnTE-2-PyP was determined not to be genotoxic or hemolytic, did not demonstrate flocculation or elicit adverse pharmacologic effects on respiration, the central nervous system (CNS), and had limited transitory effects on the cardiovascular system only at levels well above the therapeutic target dose. The intended iv clinical solution did not cause venous irritation in rabbits. The no observed adverse effect level (NOAEL) in mice was determined to be 10 mg/kg/day after 18 consecutive days of bolus iv dosing once daily in the morning. The NOAEL in monkeys after 14 days of bolus iv dosing in the morning was determined to be 5 mg/kg/day. At doses relevant to clinical use in humans, neither study revealed any indication of any specific target organ toxicity, including the classic heme porphyrin kidney, liver, CNS, or cardiac toxicities, or manganese toxicity. Mortality seen shortly after dosing in individual animals at higher doses was not accompanied by any organ or clinical pathology indications, suggesting a functional pharmacological-mediated effect. Based on the results of these studies, a conservative safe initial starting clinical dose of 5.0 mg (0.083 mg/kg in a 60 kg adult) was proposed for the initiation of human trials. Because of patent life issues, use of MnTE-2-PyP as a transplantation aid or radioprotective agent is not currently being pursued past the preclinical stages. It serves as a model for the clinical development of this class of drugs.

Evaluation of the toxicity of intravenous delivery of auroshell particles (gold-silica nanoshells).

Gold nanoshells (155 nm in diameter with a coating of polyethylene glycol 5000) were evaluated for preclinical biocompatibility, toxicity, and biodistribution as part of a program to develop an injectable device for use in the photothermal ablation of tumors. The evaluation started with a complete good laboratory practice (GLP) compliant International Organization for Standardization (ISO)-10993 biocompatibility program, including cytotoxicity, pyrogenicity (US Pharmacopeia [USP] method in the rabbit), genotoxicity (bacterial mutagenicity, chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus), in vitro hemolysis, intracutaneous reactivity in the rabbit, sensitization (in the guinea pig maximization assay), and USP/ISO acute systemic toxicity in the mouse. There was no indication of toxicity in any of the studies. Subsequently, nanoshells were evaluated in vivo by intravenous (iv) infusion using a trehalose/water solution in a series of studies in mice, Sprague-Dawley rats, and Beagle dogs to assess toxicity for time durations of up to 404 days. Over the course of 14 GLP studies, the gold nanoshells were well tolerated and, when injected iv, no toxicities or bioincompatibilities were identified.

Nonclinical vehicle use in studies by multiple routes in multiple species.

The laboratory toxicologist is frequently faced with the challenge of selecting appropriate vehicles or developing utilitarian formulations for use in in vivo nonclinical safety assessment studies. Although there are many vehicles available that may meet physical and chemical requirements for chemical or pharmaceutical formulation, there are wide differences in species and route of administration specific to tolerances to these vehicles. In current practice, these differences are largely approached on a basis of individual experience as there is only scattered literature on individual vehicles and no comprehensive treatment or information source. This approach leads to excessive animal use and unplanned delays in testing and development. To address this need, a consulting firm and three contract research organizations conducted a rigorous data mining operation of control (vehicle) data from studies dating from 1991 to present. The results identified 65 single component vehicles used in 368 studies across multiple species (dog, primate, rat, mouse, rabbit, guinea pig, minipig, chick embryo, and cat) by multiple routes. Reported here are the results of this effort, including maximum tolerated use levels by species, route, and duration of study, with accompanying dose limiting toxicity. Also included are basic chemical information and a review of available literature on each vehicle, as well as guidance on volume limits and pH by route and some basic guidance on nonclinical formulation development.

Are dietary supplements safe as currently regulated? The great debate.

At its 2002 annual meeting, the American College of Toxicology hosted in its series of issue sessions a symposium entitled "The Great Debate: Are Dietary Supplements Adequately Regulated to Enhance the Safety of Consumers." There were five participants in the debate, of whom three (the moderator and one advocate from either side) contributed papers. This article, reflecting the author's talk as the moderator, presents the applicable regulations, an overview, and history of the marketplaces and the range of perceived consumer safety problems.

Active drug metabolites in drug development.

Active drug metabolites discovered during the course of drug development constitute a subset of the larger issue of metabolic drug interactions, but still demand unique consideration from both an efficacy and a safety point of view. Improved technology has allowed better identification and quantification of metabolites, raising new issues to be addressed during the course of drug development. Several new molecular identities recently entering the marketplace have active metabolites, and many more are (or have been) in development. The MIST (Metabolites in Safety Testing) committee of PhRMA (Pharmaceutical Research and Manufacturers of America) has prepared a position paper (in press) on the subject, which has been widely discussed (with and by regulatory authorities) over the past three years.