Incidence of infectious complications with the combination of bendamustine and an anti-CD20 monoclonal antibody.

Combination of bendamustine (B) and rituximab (R) has been associated with opportunistic infections (OI) in case reports. This retrospective analysis evaluated the incidence, risk factors, and types of infectious complications (IC) in adults with CD20+ non-Hodgkin lymphoma who received ≥2 cycles of B and either R or ofatumumab. Infection data were collected up to 1-year post-B-based treatment.

Silica nanoparticles administered at the maximum tolerated dose induce genotoxic effects through an inflammatory reaction while gold nanoparticles do not.

While the collection of genotoxicity data and insights into potential mechanisms of action for nano-sized particulate materials (NPs) are steadily increasing, there is great uncertainty whether current standard assays are suitable to appropriately characterize potential risks. We investigated the effects of NPs in an in vivo Comet/micronucleus (MN) combination assay and in an in vitro MN assay performed with human blood. We also incorporated additional endpoints into the in vivo study in an effort to delineate primary from secondary mechanisms.

Relevance of sensitization to occupational allergy and asthma in the detergent industry.

There exists considerable historic experience of the relationship between exposure and both the induction of sensitization and the elicitation of respiratory symptoms from industrial enzymes of bacterial and fungal origin used in a wide variety of detergent products. The detergent industry in particular has substantial experience of how the control of exposure leads to limitation of sensitization with low risk of symptoms. However, the experience also shows that there are substantial gaps in knowledge, even when the potential occupational allergy problem is firmly under control, and also that the relationship between exposure and sensitization can be hard to establish.

The toxicology and immunology of detergent enzymes.

Detergent enzymes have a very good safety profile, with almost no capacity to generate adverse acute or chronic responses in humans. The exceptions are the limited ability of some proteases to produce irritating effects at high concentrations, and the intrinsic potential of these bacterial and fungal proteins to act as respiratory sensitizers, demonstrated in humans during the early phase of the industrial use of enzymes during the 1960s and 1970s. How enzymes generate these responses are beginning to become a little clearer, with a developing appreciation of the cell surface mechanism(s) by which the enzymatic activity promotes the T-helper (T(H))-2 cell responses, leading to the generation of IgE.

The hair dyes PPD and PTD fail to induce a T(H)2 immune response following repeated topical application in BALB/c mice.

1,4-Phenylenediamine (PPD) and the structurally-related 1,4-toluenediamine (PTD) are frequently used oxidative hair dye precursors that can induce a delayed-type hypersensitivity reaction known as contact allergy. Very rare cases of Type 1 (IgE-mediated) allergic responses associated with PPD or PTD have been reported among hair dye users. As part of an effort to determine if repeated dermal exposure to the dyes could induce a T-helper-2 (T(H)2) response, we used a dermal exposure regimen in mice reported to identify a T(H)2 response.

Chemical reactivity measurements: potential for characterization of respiratory chemical allergens.

Allergic diseases of the skin and respiratory tract resulting from exposure to low molecular weight chemicals remain important issues for consumer product development and occupational/environmental health. Widespread opportunities for exposure to chemical allergens require that there are available effective methods for hazard identification and risk assessment. In the search for new tools for hazard identification/characterization there has been interest in developing alternative methods that will reduce, refine or replace the need for animals.

Assessing the risk of type 1 allergy to enzymes present in laundry and cleaning products: evidence from the clinical data.

Microbial enzymes have been used in laundry detergent products for several decades. These enzymes have also long been known to have the potential to give rise to occupational type 1 allergic responses. A few cases of allergy among consumers using dusty enzyme detergents were reported in the early 1970s.

Tissue distribution of 20 nm, 100 nm and 1000 nm fluorescent polystyrene latex nanospheres following acute systemic or acute and repeat airway exposure in the rat.

Understanding tissue distribution and clearance of nanomaterials following different routes of exposure is needed for risk assessment. F344 female rats received single or multiple exposures to 20 nm, 100 nm or 1000 nm latex fluorospheres by intravenous (i.v.

Development of allergic antibody to an enzyme in a body lotion: results of an 18-month clinical study.

Use of enzymes in cosmetic products is novel and the safety of these products is not well understood. The safety of a prototype enzyme-containing body moisturizer lotion was tested via measures of skin compatibility and potential to induce protease-specific IgE antibody in a clinical study. Female, atopic subjects (n = 1,100) used body lotion containing 100 ppm protease (Y217L BPN') for 5 consecutive days per month, for 18 months.

Chemical respiratory allergy and occupational asthma: what are the key areas of uncertainty?

There is increasing concern about the association of respiratory disease with indoor air quality and environmental atmospheric pollution. Associated with this is the fact that in many countries there has been a significant increase in the prevalence of asthma. Against this background there is a need to address the toxicological, occupational and public health problems associated with the ability of some chemicals to cause allergic sensitization of the respiratory tract and occupational asthma.

Assessing the potential to induce respiratory hypersensitivity.

Acute and repeat dose inhalation studies have been an important part of the safety assessment of drugs, chemicals, and other products throughout the world for many years. It is known that damage to the respiratory tract can be triggered either by nonspecific irritation or by specific immune-mediated pathogenesis, and it is acknowledged that traditional inhalation studies are not designed to address fully the impact of the latter. It is also recognized that different types of immune-mediated responses can be triggered by different classes of compounds and that some immune reactions in the lung are life threatening.

Lack of type 1 sensitization to laundry detergent enzymes among consumers in the Philippines: results of a 2-year study in atopic subjects.

Background: Enzymes have been safely used in laundry products for many years. The risk of developing adverse responses to enzymes in laundry detergents among consumers in countries where hand laundry predominates is expected to be low.

Objectives: To understand how consumers in hand laundry markets used detergent products; to show that use of enzyme-containing detergents did not lead to sensitization in an atopic population with compromised skin; and to show that enzyme detergents did not have an adverse effect on skin condition.

Control of occupational asthma and allergy in the detergent industry.

Objective: To provide an overview of how a comprehensive preclinical, clinical, and industrial hygiene program has been successfully used to control allergy and asthma to enzymes used in the detergent industry.

Data Sources: The author performed a PubMed and ToxLine search of English-language articles with the keywords enzymes, occupational allergy, occupational asthma, detergent, and detergent industry from January 1, 1995, to January 1, 2002. Scientific meeting abstracts, books, and industry association papers on allergy and asthma in the detergent industry were also reviewed.

Occupational asthma and allergy in the detergent industry: new developments.

This review highlights the latest developments in the control of enzyme-induced occupational asthma and allergy (rhinitis and conjunctivitis) in the detergent industry. The industry has developed guidelines for the safe handling of enzymes in order to reduce the risk of occupational allergy and asthma. Those manufacturing facilities that follow all of the guidelines enjoy very low or no cases of asthma and allergy among workers exposed to enzymes.

Influence of MHC background on the antibody response to detergent enzymes in the mouse intranasal test.

The mouse intranasal test (MINT) was developed to assess the immunogenic potential of detergent enzymes. The BDF1 mouse (H-2(b/d)), a cross of C57Bl/6 (H-2(b)) x DBA/2 (H-2(d)) has been used for most of the development work. Preliminary data in the CB6F1(H-2(d/b)), a cross of Balb/c (H-2(d)) x C57Bl/6 showed that this strain was similar to the BDF1 in its response to enzymes.

Toxicology of protein allergenicity: prediction and characterization.

The ability of exogenous proteins to cause respiratory and gastrointestinal allergy, and sometimes systemic anaphylactic reactions, is well known. What is not clear however, are the properties that confer on proteins the ability to induce allergic sensitization. With an expansion in the use of enzymes for industrial applications and consumer products, and a substantial and growing investment in the development of transgenic crop plants that express novel proteins introduced from other sources, the issue of protein allergenicity has assumed considerable toxicological significance.

Immunologic cross-reactivity between respiratory chemical sensitizers: reactive dyes and cyanuric chloride.

Background: CyCl is a low molecular weight reactive chemical used as an intermediate in the production of plastics, herbicides, pharmaceuticals, and fiber-reactive dyes. It is a potent inducer of specific IgE antibody. The CyCl functionality is a structural component of monochlorotriazine and dichlorotriazine dyes.

Use of the mouse intranasal test (MINT) to determine the allergenic potency of detergent enzymes: comparison to the guinea pig intratracheal (GPIT) test.

A mouse intranasal test (MINT) was developed to determine the relative allergenicity of detergent enzymes. In this simple method, various doses of the enzymes are administered in a detergent matrix, via intranasal instillation, on days 1, 3, and 10, with serum samples collected on day 15. The sera are then analyzed for enzyme specific IgG1 antibody by an antigen specific enzyme immunoassay.

Safety assessment of enzyme-containing personal cleansing products: exposure characterization and development of IgE antibody to enzymes after a 6-month use test.

Background: Enzyme-containing personal cleansing products were being considered for the consumer market. Although enzymes have been marketed safely for many years as ingredients in laundry products, their use in a personal cleansing application represented a new type of exposure for consumers that was not supported by the historical safety data. An exposure assessment and additional safety data would be needed before marketing to ensure consumer safety.

Respiratory allergenicity of detergent enzymes in the guinea pig intratracheal test: association with sensitization of occupationally exposed individuals.

A guinea pig intratracheal test was used to set occupational operating guidelines for new enzyme proteins used in the detergent industry. In these studies, animals were intratracheally dosed with different levels of enzyme protein and sera from the animals were titered for allergic antibody to the enzyme. The amount of antibody produced to an enzyme was compared to the amount of antibody produced to the same protein doses of Alcalase, for which effective operating guidelines exist.

Proteolytic detergent enzymes enhance the allergic antibody responses of guinea pigs to nonproteolytic detergent enzymes in a mixture: implications for occupational exposure.

A guinea pig intratracheal test was developed to assess the respiratory allergenicity of enzymes used in the detergent industry. Information gained from this test was used in a process for setting operational exposure guidelines to protect worker health. Mixtures of enzyme proteins were given to guinea pigs once per week for 10 weeks to determine whether there were interactions among enzymes that affected the induction of antibody responses to each enzyme in the mixture.

Effect of influenza virus infection on ovalbumin-specific IgE responses to inhaled antigen in the rat.

Upper respiratory tract viral infections have been reported in clinical studies to serve as risk factors for allergic sensitization. In order to study the relationship linking influenza virus illnesses to development of allergy, murine models of allergen sensitization were previously employed. These models showed that lethal influenza viruses were able to trigger allergen-specific immunoglobulin E (IgE) production and to inhibit tolerance to repeated exposure to aerosolized allergen in the mouse.

Workshop overview. Identification of respiratory allergens.

A variety of chemicals and proteins can sensitize the respiratory tract. Among these are materials of industrial importance, including certain diisocyanates, acid anhydrides, reactive dyes, and enzymes. Currently, no widely accepted or well-validated methods for the prospective identification of respiratory allergens exist.

Induction of type I hypersensitivity in guinea pigs after inhalation of phthalic anhydride.

Guinea pigs were exposed through inhalation to phthalic anhydride (PA) dust at 0.5, 1.0, and 5.