The National Library of Medicine’s (NLM) Hazardous Substances Data Bank (HSDB): Background, Recent Enhancements and Future Plans

Abstract

The National Library of Medicine’s (NLM) Division of Specialized Information Services (SIS) Toxicology and Environmental Health Information Program is responsible for the management of the online Hazardous Substances Data Bank (HSDB). HSDB, a part of NLM’s Toxicology Data Network (TOXNET^®), is a file of chemical/substance information with one record for each specific chemical or substance, or for a category of chemicals or substances. Like the rest of TOXNET’s databases and other resources, HSDB is available online at no cost to global users. HSDB has approximately 5,600 chemicals and substances, with a focus on toxicology information and also on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, and related areas of likely interest to HSDB users. All data are from a core set of books, government documents, technical reports, selected primary journal literature, and other online sources of information, with a goal of linking the HSDB content to as much publicly available information as possible. HSDB’s content is peer-reviewed by a Scientific Review Panel of experts covering the scope of HSDB content. Recent enhancements include the addition of chemical structures to HSDB records, the addition of new subfields such as age groups for human data, more occupational exposure standards, and the addition of information on numerous nanomaterials. Examples of future plans include providing more exposure-related information, e.g., uses of a chemical or substance in consumer products; the addition of information summaries aimed towards consumers and other members of the public wanting to learn about a chemical or substance; more visual content such as diagrams (images) of the pathways of metabolism of a substance; and enhanced search features and navigation.

1. Introduction

HSDB is available for free 24 hours a day (www.toxnet.nlm.nih.gov). It was established over forty years ago at NLM to assist the United States Agency for Toxic Substances and Disease Registry (ATSDR) and the United States Environmental Protection Agency (EPA) in collecting, documenting and making available online information about the chemical substances found at National Priority Listing Sites (NPL) throughout the United States. The initial selection, building and review of specific chemical records were accomplished via meetings of representatives from the three organizations. Chemicals found at NPL sites included pollutants such as heavy metals and their salts, biocides, herbicides, insecticides, radionuclides, solvents, gases and intermediates, complex mixtures and pharmaceutical preparations. The information placed into a chemical specific record was extracted from books, government documents, technical reports, selected primary journal literature, and other sources of online information.^{1, 2, 3}

HSDB’s information has a broad scope, covering Human Health Effects, Emergency Medical Treatment, Animal and Human and Ecotoxicity Excerpts, Metabolism/Pharmacokinetics, Pharmacology, Environmental Fate/Exposure, Environmental Standards & Regulations, Chemical and Physical Properties, Manufacturing/Use Information, Laboratory Methods (analytical and clinical determinations), Synonyms and Formulations, and Safety Procedures. HSDB data fields are also referred to as “data elements.”

2. Chemical and substance selection

Chemicals, drugs, dietary supplements, venoms, heavy metals and other candidate compounds are evaluated and selected by the HSDB chemical selection team, an internal NLM group. Candidate chemicals are nominated by members of NLM’s staff, the public, scientific and regulatory agencies, and advisory groups. Compounds that are the center of national and international news because of an accidental or intentional release or a report of being found in food, medications and drinking water supplies or an incident of adverse effects from newly approved pharmaceutical agents are also candidates for selection by NLM staff. The selection team utilizes a rationale for chemical selection which includes: level of toxicity; human, animal, plant and aquatic exposure; amount of production and use and related factors such as regulatory status in the United States and other countries. These are examples of chemicals and substances of interest that are evaluated for inclusion in HSDB, and also for updating of existing records if that judged to be needed based on new information and understanding that could be added:

• U.S. Consumer Product Safety Commission (CPSC, www.cpsc.gov) chemical-related consumer product recalls and other CPSC efforts (recent CPSC efforts on phthalates and nanomaterials are key examples);

• U.S. Drug Enforcement Agency (DEA, www.dea.gov) lists of scheduled chemicals and chemical intermediates used in manufacture of DEA regulated drugs of abuse;

• U.S. Department of Energy’s (DOE, www.doe.gov) lists of radioactive and non-radioactive substances used at their production plants;

• U.S. National Institute of Environmental Health Sciences (NIEHS, http://ntp.niehs.nih.gov/) recent NIEHS and other U.S. Government agency efforts on nanomaterials are an example. Also, chemicals included in National Toxicology Program chemical reports;

• U.S. Department of Homeland Security (DHS, www.dhs.gov) “chemicals of interest” list; (examples include chemical warfare agents and their precursors);

• U.S. Environmental Protection Agency (EPA, www.epa.gov), such as:

  • Recent EPA and other U.S. Government agency efforts on isocyanates are a key example. Also, currently actively registered pesticides, restricted use and cancelled pesticide products banned from sale in the United States, herbicides and insecticides, high production volume chemicals, acutely toxic chemical substances, ambient and drinking water chemical contaminants, persistent chemical substances and drugs and chemicals in personal care products found in ambient and finished water supplies;

  • U. S. Food and Drug Administration (FDA, www.fda.gov) drugs currently approved in the U.S. and drugs removed from both U.S. and other international markets, drug black box warnings and cosmetic and food colorant lists along with excipients used in manufacture of food, drugs, cosmetics other consumer products;

  • U.S. National Institute of Occupational Safety and Health (NIOSH, www.cdc.gov/niosh) and U.S. Occupational Safety & Health Administration (OSHA, www.osha.gov). Chemical substances that are workplace contaminants and hazards include toxic industrial chemicals (TICs),

Non-U.S. governmental organizations which provide chemical and substance candidates for HSDB include but are not limited to the following: International Agency for the Research on Cancer (IARC, www.iarc.fr) and World Health Organization (WHO, www.who.int) (via their monographs on chemicals, drugs and biological products and International Programme on Chemical Safety (IPCS), European Chemicals Agency (ECHA, http://echa.europa.eu/) and other advisory groups and review panels, and industry groups representing cosmetics, excipients, flavorings, dyes and perfumes.

3. Data quality tags

The content found in HSDB records is labeled with data quality tags. While not a new feature, these tags provide users with a good indication of the level of scientific review which the records have undergone. PEER REVIEWED tags indicate that the data has been evaluated by NLM’s Scientific Review Panel (SRP) which is a group of outside NLM advisors who have extensive education and knowledge of chemistry, industrial hygiene, pharmacology, animal and human toxicology, atmospheric and aquatic and terrestrial fate, occupational and emergency medicine, radiobiology and related subjects. The SRP meets three times a year and examines about 350 HSDB records per year. QC (Quality Control) REVIEWED tags indicate that the data was excerpted from an original source and has been excerpted as is. An HSDB senior reviewer or an SRP subcommittee conducts a quality control review while a full peer review is pending. QC review may be utilized to expedite releasing information to the public. UNREVIEWED tags, signify that the data has not been evaluated for scientific accuracy and only excerpted as is from the source. As a general rule, public HSDB records do not include UNREVIEWED tags. These tags are utilized as part of the internal record building process unless there is a special circumstance.

4. Examples of recent enhancements

4.1 Ecotoxicity data element

A new data element was created to collect information on the potential ecotoxicity of a chemical. This includes effects on biomass, population density, mortality, morbidity and effects on microbial and aquatic and terrestrial populations of endemic species. Data found in the Ecotoxicity Excerpts is taken from abstracts of primary literature, governmental and non-governmental reports and data from texts.

4.2 Other standards, regulations, and guidelines data element

The Other Standards Regulations and Guidelines (OSRG) data element replaced a previous occupational data element. The OSRG element allows for expanded information from the United States and international organizations that may affect the U.S. Examples of expanded information sources include: Emergency Response Planning Guidelines (ERPGs) from the American Industrial Hygiene Association (AIHA), the Chemical Weapons Convention (CWC) international treaty and the European Commission (EC), International Uniform Chemical Information Database (IUCLID).

4.3 Subheadings used in HSDB data extraction

Because of the large amount of information appearing in certain HSDB data elements, it was determined that the undifferentiated narrative format which had been used previously required some degree of categorization to be of optimum use.

Two major data elements located within HSDB are the Human and Non-Human Toxicity Excerpts. In the Human Toxicity Excerpts data element, the following subheadings were created to more efficiently locate specific data:

• Human Exposure Studies - Controlled studies conducted on humans in a laboratory setting and include dermal sensitization tests. Exposure is measured, not controlled, and human biological effects are reported.

• Signs and Symptoms - Specific statements describing the signs or symptoms of chemical exposure.

• Case Reports - Exposure of a subject or subjects to the chemical, either accidentally or intentionally, with description of adverse events and treatment outcomes. Case Reports do not contain information on control subjects.

  • When data indicate, pediatric specific subheadings have been added to case reports in the Human Health Effects section. Although these pediatric subheadings are most often found under case reports, they may appear elsewhere in the record such as the Metabolism/Pharmacokinetics section. Examples include: infant, premature; infant, newborn; child; child, preschool; adolescent.

• Surveillance - A measure of chemical exposure including detailed information on specific medical tests to determine the impact on cardiac, hepatic, neurological or respiratory functions and potentially serious medical conditions. Information from poison control center data is also provided.

• Epidemiology Studies – Evaluation of the potential of a chemical to induce adverse effects on a specific group of exposed individuals compared to a control study group. Study designs include case control studies, cohort studies and meta-analysis. Biochemical or molecular epidemiologic studies that incorporate laboratory methods in analytical investigations are included. Other information may include descriptive studies examining differences in disease rates among populations in relation to age, gender, race, and differences in temporal or environmental conditions.

• Alternative and In Vitro Tests - Studies of interest that are not covered under Genotoxicity or endocrine modulation. For example, studies conducted using a human cell line.

• Genotoxicity - Studies that use in vitro and in vivo methods involving human tissues/cells to determine a genotoxic response (includes positive and negative studies).

• Biomonitoring - Studies that correlate the results of biological monitoring with exposures. Includes studies that, for example, show blood lead level concentrations or metabolites from organic chemical exposure and indications of raised levels of carbon monoxide in blood samples.

• Endocrine Modulation - Effects of exogenous chemicals that alter the synthesis, secretion, transport, binding, elimination and action of natural hormones in the body which are responsible for homeostasis, reproduction, development and behavior.

In the Non-human Toxicity Excerpts data element, the following subheadings were created: Laboratory Animals

• Acute Exposure - Studies conducted in animals for up to five days in duration.

• Subchronic or Prechronic Exposure - General study designs exposing animals to a chemical for six days to six months.

• Chronic Exposure or Carcinogenicity - General study design that exposed animals for over six months and all carcinogenicity studies regardless of the length of exposure to a chemical carcinogen.

• Neurotoxicity - Studies designed to look at neurotoxicity as an endpoint. These might include delayed occurrences of neurotoxicity.

• Developmental Neurotoxicology - Adverse effects induced during pregnancy or as a result of parental exposure that can manifest as neurotoxicity at any point in the life span of the offspring.

• Behavioral Studies - Objective study of animal behavior following exposure to a chemical substance.

• Alternative and In Vitro Tests - In vitro studies of interest not covered under endocrine modulation. It covers all tests validated by ICCVAM and its European counterpart.

• Genotoxicity - All genotoxicity tests regardless of the species/microorganism used except those conducted with a human cell line, for example, Salmonella typhimurium and in vivo micronucleus assay in mice.

• Endocrine Modulation - Exogenous agents that alter the synthesis, secretion, transport, binding, action or elimination of natural hormones in the body which are responsible for the maintenance or homeostasis, reproduction, development and or behavior.

• Veterinary Case Reports - Domestic animal poisonings, whether in the field or a household, for example, the accidental ingestion of antifreeze liquid by cats and dogs.

In the Ecotoxicity Excerpts data element, the following subheadings were created:

• Birds and Mammals - All wild birds and mammals affected by the chemical except for animals being raised for food. Studies are conducted both in the field and laboratory.

• Aquatic Species - Fish, algae, or protozoans affected by the chemical in the natural environment. Studies are conducted in the field and laboratory.

• Other Terrestrial Species - Effects of a chemical on non-target invertebrate insects or vertebrates not covered under Birds and Mammals such as snakes and other reptiles that are commonly used to determine the effects of the chemical in the environment.

• Field Studies - Ecological assessments of biological organization and populations, communities and ecosystems studies conducted to assess the adverse effect of a chemical substance.

• Accidental Poisonings - Applies to wildlife and covers events like fish kills which may be accidental or intentional.

5. Other significant enhancements to HSDB

5.1 Nanomaterials

The use of nanomaterials in consumer products such as clothing, building materials, electronics, medical instruments and medical treatment modalities has been of global interest to consumers, scientists, regulatory agencies, industry, and others. NLM examined a wide range of sources of information and developed records for the following nanomaterials: silver nanoparticles, iron nanoparticles, zinc oxide nanoparticles, cerium oxide nanoparticles, carbon nanotubes, titanium oxide nanoparticles, and fullerenes. These nanotechnology products were added to HSDB in 2009. More recently, records were added in 2012 for gold nanoparticles and platinum nanoparticles. All nanomaterial records include information concerning use, chemical and physical properties, human and non-human toxicology, and environmental fate.

Nanomaterial information, such as the HSDB records, is critical for stakeholders to acquire essential knowledge to address health and ecological implications. The U.S. Environmental Protection Agency (EPA) is working in the field of nanomaterials including conducting environmental assessments and publishing case studies³. The current HSDB records cover two major types of nanomaterials: carbon-based and metal-based. The recent addition of nanomaterial information to HSDB is, in part, an effort to continue the NLM function of serving as a national information resource and supporting biomedical research.

5.2 North American Poisonous Scorpion/Spider/Snake Venoms

Bites from scorpions, snakes and spiders occur throughout the world. Some bites are harmless while others cause severe morbidity and mortality. New HSDB records were built for several North American venomous animals: North American Agkistrodon (Snake Venoms) which includes copperheads and water moccasins (cottonmouth snakes); North American Centruoides (Black Scorpion Venom); North American Loxosceles (Recluse Spider Venom) and North American Latrodectus (Widow Spider Venom).

6. Future enhancements to HSDB

Following a needs assessment completed in 2012, the HSDB team is planning future enhancements to the database. The team has implemented initial enhancements and these efforts will continue. The enhancements will focus on expanding content, improving user experience, expanding user audience, and increasing speed of information delivery. Also, a major focus will be in adding visual content such as diagrams (images) of the pathways of metabolism of a substance, photos or drawings of an animal or plant associated with a substance, and pictograms and label information required under the newly implemented Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

HSDB will also be enhanced with Scorpion, Snake and Spider antivenom antidotes and the addition of venoms from scorpions, snakes and spiders of other North American, Central American and South American venomous organisms, along with European, African, Asian and Australian organisms of interest. In addition, vaccines, both commercially available monovalent and polyvalent types, will also be added. Further, new nanomaterials and other chemicals and substances will be added, along with selective updating and enhancement of the contents of records for current chemicals and substances. For example, nanomaterials have been the focus of very active research efforts in recent years, resulting in numerous new publications to consider for addition to HSDB records.

Figure 1.

Human Toxicity Excerpts

Figure 2.

Non-Human Toxicity Excerpts

Figure 3.

Ecotoxicity Excerpts

Figure 4.

Example of a nanomaterial record

Figure 5.

Example of a snake or spider record

Abbreviations

ATSDR

Agency for Toxic Substances and Disease Registry

CPSC

Consumer Product Safety Commission

DEA

Drug Enforcement Agency

DHS

Department of Homeland Security

EPA

Environmental Protection Agency

ECHA

European Chemicals Agency

FDA

Food and Drug Administration

HSDB

Hazardous Substances Data Bank

IARC

International Agency for the Research on Cancer

IPCS

International Programme on Chemical Safety

NIEHS

National Institute of Environmental Health Sciences

NIOSH

National Institute of Occupational Safety and Health

NLM

National Library of Medicine

OSHA

Occupational Safety & Health Administration

QC

Quality Control

TICs

toxic industrial chemicals

TOXNET^®

Toxicology Data Network

WHO

World Health Organization