Bulletin Board May 12, 2006

Environmental
2003 Assessment of PCDDs-PCDFs emissions from

the COPESUL/South Petrochemical complex located in

southern Brazil

2006-04-24

This study seeks to validate and confirm the results and diagnosis regarding

the potential sources of polychlorinated dibenzodioxin/dibenzofurans from

the COPESUL/South Petrochemical complex. Sources of the dibenzodioxin/

dibenzofurans were previously reported to have come from the wastewater

effluents and sewage sludge from the waste water treatment facility. The

results revealed that none of these emission sources of PCDD/Fs from the

Petrochemical Complex can be regarded as significant sources. Along the

same trend, none of the two potentially impacted environmental matrixes

monitored for PCDD/Fs for this project are showing significant impact, with

the exception of one sediment sampling point located in Lagoon 1 (tertiary

treatment) of the Complex wastewater treatment facility. The concentration

measured is above the Canadian guideline but below the PEL guideline,

which according to the definitions of the guidelines means that adverse

biological effect is possibly occurring.

Authors: Deschamps, Marc; Allard, Jean-Luc; Rangel, Carla M. P.; Ribeiro,

Claudia; Dos Santos, Sepe T. F.

Full Source: Organohalogen Compounds [computer optical disk] 2004,

66(Dioxin 2004), 1586-1591(Eng).
Excretion and ecotoxicity of pharmaceutical and personal

care products in the environment.

2006-04-24

This literature reviews the presence and fate of pharmaceutical and

personal care products (PPCPs) in the environment. The existing clinical

pharmacokinetics and pharmacodynamics data for 81 common compounds

were examined. for cues of ecotoxicity. The results showed that more than

half of the compounds evaluated have low or moderately low proportions

of the parent compounds excreted. However, the proportions excreted

were negatively but moderately correlated, with the concentration of the

compounds in the aquatic environment, suggesting that the compounds that

have low proportions excreted may also have inherently low degradability

in the environment. The authors concluded that PPCPs occur in low

concentration. in the environment and are unlikely to elicit acute toxicity.

An ecotoxicity potential that is based on chronic toxicity, bioavailability, and

duration of exposure to nontarget organisms is described as a guide in

assessing the potency of these compounds in the environment.

Author: Jjemba, Patrick K.

Full Source: Ecotoxicology and Environmental Safety 2006, 63(1), 113-130

(Eng)
Continuous environmental radiation monitoring network

at Kalpakkam: past perspective and future vision

2006-04-24

This study reviews the environmental radiation monitoring network at

Kalpakkam. The environmental radiation monitoring network at Kalpakkam

has been in continuous operation for more than a decade. A number of

environmental radiation monitoring stations were installed at various locations

in the DAE complex at Kalpakkam and the environmental radiation data

analyzed and archived. Initially two independent detector systems, based

on High Pressure Ionization Chamber (HPIC) and energy compensated

GM were used. A Commercially available Gamma tracer was later installed

along with HPICs and GM systems. The results from the studies lead to the

development of a instrument which operates on a battery backed up inverter

with solar powered charging and trickle charged from mains. The system is

based on embedded system with energy compensated GM as a detector

with on line real time information and dose rate data displayed in 16?2 LCD

module. As part of intensive developmental study in radiological dispersion

modeling and its validation being undertaken in RSD, Safety Group, the

above network is now being upgraded and expanded with additional stations

being put up to cover more areas/sectors. Real time data access from

these stations using RF network is installed. This would help in radiological

prediction and mapping in the event of normal and off-normal situations. In

addn., portable survey instrument with inbuilt GPS facility and data storage

in flash card is being designed and developed.

Authors: Prakash, G. Surya; Mathiyarasu, R.; Somayaji, K. M.

Full Source: Indira Gandhi Centre for Atomic Research, Kalpakkam, [Report]

IGC 2005, (IGC 270), i-vi, 1-30 (Eng).

Medical
Cellular uptake and cytotoxic potential of respirable

bentonite particles with different quartz contents and

chemical modifications in human lung fibroblasts

2006-04-25

This study investigated the cellular uptake and the cytotoxic potential

of bentonite particles with an R-quartz content of up to 6% and different

chemical modifications (activation: alkaline, acidic, organic) in human lung

fibroblasts (IMR90). The ability of the particles to induce apoptosis in IMR90-

cells and the hemolytic activity was also tested. The results demonstrated

that activated bentonite particles are better taken up by IMR90-cells than

untreated (native) bentonite particles. Also, activated bentonite particles

with a quartz content of 5-6% were more cytotoxic than untreated bentonites

or bentonites with a quartz content lower than 4%. The bentonite samples

induced necrotic as well as apoptotic cell death. In general, bentonites

showed a high membrane-damaging potential shown as hemolytic activity in

human erythrocytes. The authors conclude that cellular effects of bentonite

particles in human lung cells are enhanced after chemical treatment of

the particles. The cytotoxic potential of the different bentonites is primarily

characterized by a strong lysis of the cell membrane.

Authors: Geh, Stefan; Yuecel, Raif; Duffin, Rodger; Albrecht, Catrin; Borm,

Paul J. A.; Armbruster, Lorenz; Raulf-Heimsoth, Monika; Bruening, Thomas;

Hoffmann, Eik; Rettenmeier, Albert W.; Dopp, Elke

Full Source: Archives of Toxicology 2006, 80(2), 98-106 (Eng)
A pilot clinical trial of a recombinant ricin vaccine in

normal humans

2006-04-25

This study examines the use of a recombinant ricin vaccine in humans

to protect against the toxic effects of Racin. Ricin,is a highly potent toxin

produced by castor beans and contains a lectin-binding B chain and

a ribotoxic A chain (RTA). It also contains a separate site on RTA that is

responsible for inducing vascular leak syndrome (VLS) in humans. In this

study, recombinant RTA with two amino acid substitutions that disrupt its

ribotoxic site (Y80A) and its VLS-inducing site (V76M) were developed. This

mutant recombinant RTA (named RiVax) was expressed and produced in

Escherichia coli and purified. The clinical trial involved three groups of five

normal volunteers being injected three times at monthly intervals with 10,

33, or 100 Ìg of RiVax. The results showed that the vaccine was safe and

elicited ricin-neutralizing antibodies in one of five individuals in the low-dose

group, four of five in the intermediate dose group, and five of five in the

high-dose group. The authors conclude that these results justified further

development of the vaccine.

Authors: Vitetta, Ellen S.; Smallshaw, Joan E.; Coleman, Elaine; Jafri,

Hasan; Foster, Callie; Munford, Robert; Schindler, John

Full Source: Proceedings of the National Academy of Sciences of the United

States of America 2006, 103(7), 2268-2273 (Eng)
Monitoring dioxins and furans in subjects living in the

vicinity of a hazardous waste incinerator after 4 years of

operation

2006-04-25

In 1996, construction of a hazardous waste incinerator (HWI) was initiated

in Constanti, Tarragona, Spain. Regular operations in the facility started in

1999. A biological monitoring program was designed to establish the potential

health risks of polychlorinated dibenzo-p-dioxin and furan (PCDD/PCDF)

exposure on the general population living near the new HWI. Samples of

blood, breast milk and adipose tissue were obtained during the construction

period of the HWI from subjects living in the neighborhood of the facility

and analyzed for baseline levels of PCDD/PCDF. This study determines

the concentration of dioxin and furan in subjects living in the vicinity after

4 years of operation by HWI. Biological samples were again collected, and

PCDD/PCDF concentrations determined. The concentration of PCDD/

PCDF in the biological samples from subjects living in the vicinity of the HWI

are presented. The dietary intake of these compounds by the population

in this area, after 4 years of regular operations, is also shown. Results are

compared with baseline PCDD/PCDF levels obtained in 1999.

Authors: Bocio, Ana; Domingo, Jose Luis; Garcia, Francisco; Schuhmacher,

Marta; Llobet, Joan Maria

Full Source: Organohalogen Compounds [computer optical disk] 2004,

66(Dioxin 2004), 2507-2512 (Eng)
Drug-induced Q-T prolongation

2006-04-25

This literature reviews the possibility that drug therapy may induce Q-

T prolongation by alteration of potassium ion currents in cardiac cells,

resulting in abnormal repolarization. Q-T prolongation, whether congenital

or acquired, has been associated with the development of the malignant

dysrhythmia Torsade de Pointes (TdP), which may result in sudden death.

Recent regulatory actions and drug withdrawals due to Q-T prolongation

or TdP have focused attention on this issue. Both patient and medication

factors contribute to the individual risk of drug-induced Q-T prolongation or

TdP. The authors conclude that clinicians should be aware of these issues

when prescribing new drugs and should weigh the risks and benefits carefully

when prescribing drugs known to prolong the Q-T interval.

Authors: Kao, Louise W.; Furbee, R. Brent

Full Source: Medical Clinics of North America 2005, 89(6), 1125-1144

(Eng)
Pharmacokinetics, thrombogenicity and safety of a

double viral inactivated factor IX concentrate compared

with a prothrombin complex concentrate

2006-04-25

Therapeutic options for developing countries have to assure an optimum

safety and efficacy and low-cost antihaemophilic concentration. This

was carried out in 12 previously treated HB patients, comparing the

pharmacokinetics (PK), thrombogenicity(TG) and safety of two plasma-

derived double-inactivated factor IX (FIX) concentrations, UMAN COMPLEX

DI (product A) [plasma-derived prothrombin concentrations (PCC)] and a

high purity FIX conc. AIMAFIX DI (product B, HPFIX). In a non-bleeding

state, they received one single i.v. dose FIX or HPFIX, and after a wash-out

period of 14 days, the other product. The acute tolerance was evaluated

and the PK parameters based on FIX levels were detected. Ten cases

remained in on-demand treatment for 6 months, five with PCC and five with

HPFIX. PK and anti-FIX inhibitors were repeated at 3 and 6 months. No

inhibitors were detected. The results showed HPFIX had significantly lower

IR and higher CL. There were no differences in PK at 3 and 6 months. In

TG, significant increments in TAT and F1 + 2 at 30 min and 6 h were found

with PCC. Product B PK results agrees with reported results for other HPFIX

prepations. Use of PCC product A has to consider its thrombogenic activity.

Authors: Ruiz-Saez, A.; Hong, A.; Arguello, A.; Echenagucia, M.; Boadas,

A.; Fabbrizzi, F.; Minichilli, F.; De Bosch, N. B.

Full Source: Haemophilia 2005, 11(6), 583-588 (Eng), Blackwell Publishing

Ltd.
Medical Study on safety of the antimalarial combination of

piperaquine phosphate and dihydroartemisinin produced

in Vietnam

2006-04-25

This study investigated the sub-chronic toxicity of an antimalarial combination

between piperaquine phosphate (PQP, 320mg) and dihydroartemisinin

(DHA, 40mg) in rabbits to determine its safety. The combination drug, at

the doses of 64 and 100 mg of (PQP+ DHA)/kg of body wt. per day for 28

consecutive days, was administered orally. The influences of the drug on

rabbits’ laboratory indexes and weights was observed during and after the

treatment. The results showed that rabbits treated with (PQP +DHA) by oral

administration acted and ate normally. At the doses of 64 and 100 mg of

(PQP + DHA)/kg per day the body weights of rabbits increased significantly.

At 64 mg/kg per day the biochemical and hematological indexes did not

change significantly. At the treated dose of 100 mg/kg per day the biochemical

indexes and some hematological indexes did not change significantly

through the study period but protein and monocytes increased significantly

on day 28. The authors concluded that the combination drug did not affect

the laboratory indexes of these rabbits at the treatment doses.

Authors: Thuan, Le Khanh; Nhu, Truong Van; Nhan, Doan Hanh; Nguyen,

Thi Minh Thu; Nguyen, Van Hung

Full Source: Tap Chi Duoc Hoc 2005, 45(11), 16-19 (Viet)
Safety of prolonged therapy with bortezomib in relapsed

or refractory multiple myeloma

2006-04-25

Bortezomib, a first-in-class proteasome inhibitor, is active with manageable

toxicities in relapsed and/or refractory myeloma. This literature looks at

the safety of prolonged therapy with bortezomib in relapsed or refractory

multiple myeloma. Sixty-Three patients with relapsed and/or refractory

myeloma were treated with bortezomib 1.0 or 1.3 mg/m2 on days 1, 4, 8,

and 11 every 21 days for up to 8 cycles. Dexamethasone could be added

because of progressive disease after 2 cycles or stable disease after 4

cycles. Continuation of or retreatment with bortezomib was offered to

patients who would benefit from extended treatment. The results showed

that seventy-eight percent of patients completed this study at the same

or higher bortezomib dose than they started on during this study, and the

treatment schedule of twice-weekly administration remained unchanged in

89%. The safety profile was similar between the extension and parent trials,

with no evidence of new cumulative toxicity. The most commonly reported

Grade 3/4 toxicities were thrombocytopenia (29%), with a consistent pattern

of recovery during the rest period of each cycle, diarrhea (11%), anemia

(11%), and neutropenia (10%). Neuropathy was reported less frequently.

The authors concluded that retreatment with or continuation of bortezomib

beyond 6 months was safe, and toxicities were manageable, in patients with

relapsed and/or refractory myeloma.

Authors: Berenson, James R.; Jagannath, Sundar; Barlogie, Bart; Siegel,

David T.; Alexanian, Raymond; Richardson, Paul G.; Irwin, Daviid; Alsina,

Melissa; Rajkumar S. Vincent; Srkalovic, Gordon; Singhal, Seema;

Limentani, Steven; Niesvizky, Ruben; Esseltine, Dixie L.; Trehu, Elizabeth;

Bortezomib,

Schenkein, David P.; Anderson, Kenneth

Full Source: Cancer (New York, NY, United States) 2005, 104(10), 2141-

2148 (Eng)
Second-Generation Replication-Competent Oncolytic

Adenovirus Armed with Improved Suicide Genes and ADP

Gene Demonstrates Greater Efficacy without Increased

Toxicity.

2006-04-25

Replication-competent adenovirus-mediated suicide gene therapy has

proven to be safe in humans when delivered intraprostatically. Although

signs of efficacy are emerging, it is likely that further improvements will

be needed before this technology will have widespread applicability in the

clinic. This study developed a second-generation, replication competent

adenovirus (Ad5-yCD/mutTKSR39 rep-ADP) containing an improved yeast

cytosine deaminase (yCD)/mutantSR39 herpes simplex virus thymidine

kinase fusion (yCD/mutTKSR39) gene and the adenovirus death protein

(ADP) gene. Relative to the first-generation The use of the Ad5-CD/TKrep

adenovirus, Ad5-yCD/mutTKSR39 rep-ADP demonstrated greater tumor

cell kill in vitro and significantly greater tumor control in preclinical models of

human cancer. When the transgene volume was followed by direct injection

of adenovirus into human tumor xenografts and also the naive canine

prostate it demonstrated that ADP enhanced adenoviral spread in vivo.

Toxocological studues performed did not show any significant increase in

toxicity relative to the parental Ad5-CD/Tkrep. Adenovirus with the improved

yCD/mutTKSR39 fusion and ADP genes. The authors conclude that these

results provide the scientific basis for evaluating the safety and efficacy of the

second-generation Ad5-yCD/mutTKSR39 rep-ADP adenovirus in humans.

Authors: Barton, Kenneth N.; Paielli, Dell; Zhang, Yingshu; Koul, Sweaty;

Brown, Stephen L.; Lu, Mei; Seely, John; Kim, Jae Ho; Freytag, Svend O.

Full Source: Molecular Therapy 2006, 13(2), 347-356 (Eng)